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1.
Biol Psychiatry ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33975707

RESUMO

BACKGROUND: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. METHODS: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. RESULTS: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. CONCLUSIONS: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.

2.
Transl Psychiatry ; 11(1): 254, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33927182

RESUMO

Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R2 = 0.06, p = 2 × 10-5) and current stress measured by Perceived Stress Scale (R2 = 0.13, p < 1 × 10-6) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R2 = 0.41, p < 1 × 10-6). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h2) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h2 for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.

3.
Am J Med Genet B Neuropsychiatr Genet ; 186(2): 113-121, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650257

RESUMO

Sleep is essential to the human brain and is regulated by genetics with many features conserved across species. Sleep is also influenced by health and environmental factors; identifying replicable genetic variants contributing to sleep may require accounting for these factors. We examined how stress and mood disorder contribute to sleep and impact its heritability. Our sample included 326 Amish/Mennonite individuals with a lifestyle with limited technological interferences with sleep. Sleep measures included Pittsburgh Sleep Quality Index (PSQI), bedtime, wake time, and time to sleep onset. Current stress level, cumulative life stressors, and mood disorder were also evaluated. We estimated the heritability of sleep features and examined the impact of current stress, lifetime stress, mood diagnosis on sleep quality. The results showed current stress, lifetime stress, and mood disorder were independently associated with PSQI score (p < .05). Heritability of PSQI was low (0-0.23) before and after accounting for stress and mood. Bedtime, wake time, and minutes to sleep time did show significant heritability at 0.44, 0.42, and 0.29. However, after adjusting for shared environment, only heritability of wake time remained significant. Sleep is affected by environmental stress and mental health factors even in a society with limited technological interference with sleep. Wake time may be a more biological marker of sleep as compared to the evening measures which are more influenced by other household members. Accounting for nongenetic and partially genetic determinants of sleep particularly stress and mood disorder is likely important for improving the precision of genetic studies of sleep.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33558674

RESUMO

Despite strong evidence of heritability and growing discovery of genetic markers for major mental illness, little is known about how gene expression in the brain differs across psychiatric diagnoses, or how known genetic risk factors shape these differences. Here we investigate expressed genes and gene transcripts in postmortem subgenual anterior cingulate cortex (sgACC), a key component of limbic circuits linked to mental illness. RNA obtained postmortem from 200 donors diagnosed with bipolar disorder, schizophrenia, major depression, or no psychiatric disorder was deeply sequenced to quantify expression of over 85,000 gene transcripts, many of which were rare. Case-control comparisons detected modest expression differences that were correlated across disorders. Case-case comparisons revealed greater expression differences, with some transcripts showing opposing patterns of expression between diagnostic groups, relative to controls. The ~250 rare transcripts that were differentially-expressed in one or more disorder groups were enriched for genes involved in synapse formation, cell junctions, and heterotrimeric G-protein complexes. Common genetic variants were associated with transcript expression (eQTL) or relative abundance of alternatively spliced transcripts (sQTL). Common genetic variants previously associated with disease risk were especially enriched for sQTLs, which together accounted for disproportionate fractions of diagnosis-specific heritability. Genetic risk factors that shape the brain transcriptome may contribute to diagnostic differences between broad classes of mental illness.

5.
Sci Rep ; 11(1): 1155, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441847

RESUMO

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

6.
Pharmacopsychiatry ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33147643

RESUMO

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

7.
Transl Psychiatry ; 10(1): 298, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839438

RESUMO

Bipolar disorder is often comorbid with anxiety, which is itself associated with poorer clinical outcomes, including suicide. A better etiologic understanding of this comorbidity could inform diagnosis and treatment. The present study aims to test whether comorbid anxiety in bipolar disorder reflects shared genetic risk factors. We also sought to assess the contribution of genetic risk for anxiety to suicide attempts in bipolar disorder. Polygenic risk scores (PRS) were calculated from published genome-wide association studies of samples of controls and cases with anxiety (n = 83,566) or bipolar disorder (n = 51,710), then scored in independent target samples (total n = 3369) of individuals with bipolar disorder who reported or denied lifetime anxiety disorders or suicidal attempts in research interviews. Participants were recruited from clinical and nonclinical settings and genotyped for common genetic variants. The results show that polygenic risk for anxiety was associated with comorbid anxiety disorders and suicide attempts in bipolar disorder, while polygenic risk for bipolar disorder was not associated with any of these variables. Our findings point out that comorbid anxiety disorders in bipolar disorder reflect a dual burden of bipolar and anxiety-related genes; the latter may also contribute to suicide attempts. Clinical care that recognizes and addresses this dual burden may help improve outcomes in people living with comorbid bipolar and anxiety disorders.

8.
J Psychiatr Res ; 123: 159-163, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32065952

RESUMO

The Mood Disorder Questionnaire (MDQ) is an established screening tool for bipolar spectrum disorders (BSD), but has not been validated in diverse populations and the best scoring method remains uncertain. This study assessed diagnostic validity of the MDQ among Anabaptists, an underserved population frequently involved in genetic research. 161 participants completed the MDQ and were diagnosed by a best-estimate final diagnosis (BEFD). Diagnostic agreements between alternate MDQ scoring methods and the BEFD were quantified using Cohen's Kappa (κ), sensitivity (α), and specificity (ß). Scoring criteria evaluated included >7 simultaneous symptoms and at least moderate impairment, >7 simultaneous symptoms, with at least mild impairment, >7 symptoms only, with no further requirement, and three novel scoring methods that require >5 symptoms or fewer. Diagnostic agreement varied. The original method proved most specific but had the lowest κ and sensitivity. κ increased with more liberal scoring criteria, reaching a maximum under the lower-threshold symptom methods, with little loss of specificity in the 5-symptom method. Decreasing the symptom threshold below 5 conferred little or no benefit. These results support the diagnostic validity of the MDQ among this Anabaptist sample and suggest that a 5-symptom scoring method may increase diagnostic sensitivity in populations at high risk for bipolar disorder.

9.
Mol Psychiatry ; 25(3): 544-559, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31907381

RESUMO

Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.

10.
Mol Psychiatry ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712720

RESUMO

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

11.
Transl Psychiatry ; 9(1): 228, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527585

RESUMO

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h2 = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h2 = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.


Assuntos
Alelos , Transtorno Bipolar/diagnóstico , Predisposição Genética para Doença , Genótipo , Fenótipo , Adulto , Transtorno Bipolar/genética , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Escalas de Graduação Psiquiátrica , Adulto Jovem
13.
Mol Psychiatry ; 24(11): 1576-1582, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31164699

RESUMO

The Genomics Workgroup of the National Advisory Mental Health Council (NAMHC) recently issued a set of recommendations for advancing the NIMH psychiatric genetics research program and prioritizing subsequent follow-up studies. The report emphasized the primacy of rigorous statistical support from properly designed, well-powered studies for pursuing genetic variants robustly associated with disease. Here we discuss the major points NIMH program staff consider when assessing research applications based on common and rare variants, as well as genetic syndromes, associated with psychiatric disorders. These are broad guiding principles for investigators to consider prior to submission of their applications. NIMH staff weigh these points in the context of reviewer comments, the existing literature, and current investments in related projects. Following the recommendations of the NAMHC, statistical strength and robustness of the underlying genetic discovery weighs heavily in our funding considerations as does the suitability of the proposed experimental approach. We specifically address our evaluation of applications motivated in whole, or in part, by an association between human DNA sequence variation and a disease or trait relevant to the mission of the NIMH.


Assuntos
Genômica/tendências , Transtornos Mentais/genética , Saúde Mental/tendências , Humanos , National Institute of Mental Health (U.S.) , Estados Unidos
15.
Mol Psychiatry ; 24(4): 613-624, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30135510

RESUMO

Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human-induced pluripotent stem cells (iPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. IPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). VPA had the greatest effects on TRANK1 expression in iPSC, NPC, and astrocytes. Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs906482, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics.


Assuntos
Citocinas/genética , Células-Tronco Neurais/efeitos dos fármacos , Ácido Valproico/farmacologia , Alelos , Astrócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ácido Valproico/metabolismo
16.
Genet Epidemiol ; 43(2): 189-206, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30537345

RESUMO

We develop linear mixed models (LMMs) and functional linear mixed models (FLMMs) for gene-based tests of association between a quantitative trait and genetic variants on pedigrees. The effects of a major gene are modeled as a fixed effect, the contributions of polygenes are modeled as a random effect, and the correlations of pedigree members are modeled via inbreeding/kinship coefficients. F -statistics and χ 2 likelihood ratio test (LRT) statistics based on the LMMs and FLMMs are constructed to test for association. We show empirically that the F -distributed statistics provide a good control of the type I error rate. The F -test statistics of the LMMs have similar or higher power than the FLMMs, kernel-based famSKAT (family-based sequence kernel association test), and burden test famBT (family-based burden test). The F -statistics of the FLMMs perform well when analyzing a combination of rare and common variants. For small samples, the LRT statistics of the FLMMs control the type I error rate well at the nominal levels α = 0.01 and 0.05 . For moderate/large samples, the LRT statistics of the FLMMs control the type I error rates well. The LRT statistics of the LMMs can lead to inflated type I error rates. The proposed models are useful in whole genome and whole exome association studies of complex traits.


Assuntos
Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Modelos Genéticos , Característica Quantitativa Herdável , Simulação por Computador , Família , Humanos , Modelos Lineares , Miopia/genética
17.
Eur Neuropsychopharmacol ; 29(1): 156-170, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503783

RESUMO

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Idoso , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Escalas de Graduação Psiquiátrica , Adulto Jovem
18.
Mol Psychiatry ; 24(4): 523-535, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29955165

RESUMO

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.


Assuntos
Família/psicologia , Transtornos Mentais/genética , Alelos , Frequência do Gene/genética , Variação Genética/genética , Genótipo , Humanos , Saúde Mental , Linhagem , Fenótipo , Projetos de Pesquisa , Tamanho da Amostra , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
19.
Transl Psychiatry ; 8(1): 280, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30552317

RESUMO

Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Ketamina/uso terapêutico , Testes Farmacogenômicos , Escopolamina/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
20.
Int J Bipolar Disord ; 6(1): 24, 2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30415424

RESUMO

BACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.

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