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1.
Proc Natl Acad Sci U S A ; 120(11): e2214834120, 2023 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-36893272

RESUMEN

Human cortical expansion has occurred non-uniformly across the brain. We assessed the genetic architecture of cortical global expansion and regionalization by comparing two sets of genome-wide association studies of 24 cortical regions with and without adjustment for global measures (i.e., total surface area, mean cortical thickness) using a genetically informed parcellation in 32,488 adults. We found 393 and 756 significant loci with and without adjusting for globals, respectively, where 8% and 45% loci were associated with more than one region. Results from analyses without adjustment for globals recovered loci associated with global measures. Genetic factors that contribute to total surface area of the cortex particularly expand anterior/frontal regions, whereas those contributing to thicker cortex predominantly increase dorsal/frontal-parietal thickness. Interactome-based analyses revealed significant genetic overlap of global and dorsolateral prefrontal modules, enriched for neurodevelopmental and immune system pathways. Consideration of global measures is important in understanding the genetic variants underlying cortical morphology.


Asunto(s)
Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética , Adulto , Humanos , Corteza Cerebral/anatomía & histología , Corteza Prefrontal , Encéfalo
2.
BMC Cancer ; 23(1): 151, 2023 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-36782147

RESUMEN

BACKGROUND: This retrospective cohort study examined the impact of tetracyclines (TCs) and proton pump inhibitors (PPIs) alone or in combination on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with NSCLC treated with gefitinib or erlotinib for at least 1 week between January 2009 and October 2021 were enrolled and divided into four groups based on the presence/absence of TC and/or PPI in the therapeutic regimen: TC-/PPI-, TC + /PPI-, TC-/PPI + , TC + /PPI + . Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively. RESULTS: The estimated median PFS and OS of 347 included patients with NSCLC were 8.57 (95% confidence interval [CI]: 7.66-9.48) months and 13.10 (95% CI: 11.03-15.17) months, respectively. Co-administration of EGFR-TKIs with PPIs decreased the PFS and OS, while that with TCs improved the PFS and OS. However, the concomitant use of EGFR-TKIs, TCs, and PPIs yielded survival rates similar to that of EGFR-TKI therapy alone. CONCLUSIONS: The administration of EGFR-TKIs with other drugs poses a challenge in managing patients with NSCLC. Therefore, reassessing the indications and necessity of TC or PPI therapy is essential for patients receiving erlotinib or gefitinib. The benefits and risks of possible discontinuation due to the clinical relevance of this interaction should be considered.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Quinazolinas , Estudios Retrospectivos , Tetraciclinas/uso terapéutico
3.
PLoS Comput Biol ; 18(2): e1009903, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35213535

RESUMEN

Integration of multi-omics data with molecular interaction networks enables elucidation of the pathophysiology of Alzheimer's disease (AD). Using the latest genome-wide association studies (GWAS) including proxy cases and the STRING interactome, we identified an AD network of 142 risk genes and 646 network-proximal genes, many of which were linked to synaptic functions annotated by mouse knockout data. The proximal genes were confirmed to be enriched in a replication GWAS of autopsy-documented cases. By integrating the AD gene network with transcriptomic data of AD and healthy temporal cortices, we identified 17 gene clusters of pathways, such as up-regulated complement activation and lipid metabolism, down-regulated cholinergic activity, and dysregulated RNA metabolism and proteostasis. The relationships among these pathways were further organized by a hierarchy of the AD network pinpointing major parent nodes in graph structure including endocytosis and immune reaction. Control analyses were performed using transcriptomics from cerebellum and a brain-specific interactome. Further integration with cell-specific RNA sequencing data demonstrated genes in our clusters of immunoregulation and complement activation were highly expressed in microglia.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Redes Reguladoras de Genes/genética , Estudio de Asociación del Genoma Completo , Genómica , Ratones , Transcriptoma/genética
4.
Mol Psychiatry ; 25(3): 692-695, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30705424

RESUMEN

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

5.
Mol Psychiatry ; 25(3): 584-602, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-30283035

RESUMEN

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ß = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ß = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.


Asunto(s)
Trastorno Autístico/genética , Ganglios Basales/patología , Trastornos de los Cromosomas/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidad Intelectual/genética , Adulto , Trastorno del Espectro Autista/genética , Encéfalo/patología , Deleción Cromosómica , Duplicación Cromosómica , Cromosomas Humanos Par 16/genética , Bases de Datos Factuales , Femenino , Globo Pálido/patología , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Trastornos del Neurodesarrollo/genética , Tamaño de los Órganos/genética , Putamen/patología , Esquizofrenia/genética
6.
J Am Acad Dermatol ; 84(6): 1782-1791, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32828861

RESUMEN

BACKGROUND: Patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have high mortality rates. Disseminated intravascular coagulation has been reported in SJS/TEN patients. The influence of this lethal complication in patients with SJS/TEN is not well known. OBJECTIVE: This study aimed to investigate the risk and outcomes of disseminated intravascular coagulation in patients with SJS/TEN. METHODS: We analyzed the disseminated intravascular coagulation profiles of patients receiving a diagnosis of SJS/TEN between 2010 and 2019. RESULTS: We analyzed 150 patients with SJS/TEN (75 with SJS, 22 with overlapping SJS/TEN, and 53 with TEN) and their complete disseminated intravascular coagulation profiles. Disseminated intravascular coagulation was diagnosed in 32 patients (21.3%), primarily those with TEN. It was significantly associated with systemic complications, including gastrointestinal bleeding, respiratory failure, renal failure, liver failure, infection, and bacteremia. Additionally, SJS/TEN patients with disseminated intravascular coagulation had elevated procalcitonin levels. Among patients with SJS/TEN, disseminated intravascular coagulation was associated with a greater than 10-fold increase in mortality (78.1% vs 7%). LIMITATIONS: The study limitations include small sample size and a single hospital system. CONCLUSION: Disseminated intravascular coagulation is a potential complication of SJS/TEN and associated with higher mortality. Early recognition and appropriate management of this critical complication are important for patients with SJS/TEN.


Asunto(s)
Coagulación Intravascular Diseminada/etiología , Coagulación Intravascular Diseminada/mortalidad , Hemorragia Gastrointestinal/complicaciones , Síndrome de Stevens-Johnson/complicaciones , Síndrome de Stevens-Johnson/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/complicaciones , Bacteriemia/microbiología , Femenino , Humanos , Estimación de Kaplan-Meier , Fallo Hepático/complicaciones , Masculino , Persona de Mediana Edad , Insuficiencia Renal/complicaciones , Insuficiencia Respiratoria/complicaciones , Tasa de Supervivencia
7.
Brain ; 143(7): 2272-2280, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32591829

RESUMEN

Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.


Asunto(s)
Enfermedad de Alzheimer/genética , Herencia Multifactorial/genética , Caracteres Sexuales , Anciano , Progresión de la Enfermedad , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
8.
Cereb Cortex ; 30(10): 5597-5603, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32483632

RESUMEN

The thickness of the cerebral cortical sheet and its surface area are highly heritable traits thought to have largely distinct polygenic architectures. Despite large-scale efforts, the majority of their genetic determinants remain unknown. Our ability to identify causal genetic variants can be improved by employing brain measures that better map onto the biology we seek to understand. Such measures may have fewer variants but with larger effects, that is, lower polygenicity and higher discoverability. Using Gaussian mixture modeling, we estimated the number of causal variants shared between mean cortical thickness and total surface area, as well as the polygenicity and discoverability of regional measures. We made use of UK Biobank data from 30 880 healthy White European individuals (mean age 64.3, standard deviation 7.5, 52.1% female). We found large genetic overlap between total surface area and mean thickness, sharing 4016 out of 7941 causal variants. Regional surface area was more discoverable (P = 2.6 × 10-6) and less polygenic (P = 0.004) than regional thickness measures. These findings may serve as a roadmap for improved future GWAS studies; knowledge of which measures are most discoverable may be used to boost identification of genetic predictors and thereby gain a better understanding of brain morphology.


Asunto(s)
Corteza Cerebral/anatomía & histología , Herencia Multifactorial , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/genética
9.
J Oncol Pharm Pract ; 27(1): 63-70, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32264743

RESUMEN

BACKGROUND: Hepatitis B virus carriers who receive systemic cancer chemotherapy have been found to be at a higher risk of hepatitis B virus reactivation. However, lack of standard prophylaxis protocol resulted in life-threatening adverse events. OBJECTIVE: This retrospective study is to investigate prevalence and chemotherapy drug-induced hepatitis B virus reactivation in all types of cancer patients and establish an institutional clinical practice protocol.Methodology: This retrospective cohort study evaluated the incidence of hepatitis B virus infection, the pre-chemotherapy screening rate of hepatitis B surface antigen (HBsAg), and the severity of hepatitis B virus reactivation of cancer patients receiving intravenous chemotherapy between 2013 and 2014. Patients receiving local chemotherapy with intra-cavity instillation, drug- or alcohol-related hepatitis, or chemotherapy for immune diseases were excluded. RESULTS: In total 784 patients, 404 patients (51.53%) underwent hepatitis B virus serum antigen (HBsAg) testing before chemotherapy, and 61 patients (7.78%) tested positive. Only 32 patients (4.08%) received prophylactic hepatitis B virus antiviral therapy. Patients receiving prophylactic antiviral drugs were significantly lower risk of hepatitis B virus reactivation than nonprophylaxis (relative risk, RR: 0.53, number needed to treat, NNT: 12). Moreover, our study found specific single or combined chemotherapy that may cause hepatitis B virus reactivation different from those of other studies conducted in Western countries. The differences may refer to enzymes, proteins and immune response of patients. CONCLUSIONS: Our findings indicate that cancer patients receiving prophylactic antiviral drugs remain at risk of hepatitis B virus reactivation during chemotherapy. Therefore, the hepatitis B virus screen and chemotherapy control system was established in 2017 to reduce the risk of hepatitis B virus reactivation and improve patient safety.


Asunto(s)
Virus de la Hepatitis B , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Neoplasias/complicaciones , Neoplasias/epidemiología , Activación Viral/efectos de los fármacos , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , Femenino , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/análisis , Humanos , Incidencia , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Taiwán/epidemiología
10.
Hum Mol Genet ; 27(R1): R22-R28, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29522091

RESUMEN

Structural neuroimaging measures based on magnetic resonance imaging have been at the forefront of imaging genetics. Global efforts to ensure homogeneity of measurements across study sites have enabled large-scale imaging genetic projects, accumulating nearly 50K samples for genome-wide association studies (GWAS). However, not many novel genetic variants have been identified by these GWAS, despite the high heritability of structural neuroimaging measures. Here, we discuss the limitations of using heritability as a guidance for assessing statistical power of GWAS, and highlight the importance of discoverability-which is the power to detect genetic variants for a given phenotype depending on its unique genomic architecture and GWAS sample size. Further, we present newly developed methods that boost genetic discovery in imaging genetics. By redefining imaging measures independent of traditional anatomical conventions, it is possible to improve discoverability, enabling identification of more genetic effects. Moreover, by leveraging enrichment priors from genomic annotations and independent GWAS of pleiotropic traits, we can better characterize effect size distributions, and identify reliable and replicable loci associated with structural neuroimaging measures. Statistical tools leveraging novel insights into the genetic discoverability of human traits, promises to accelerate the identification of genetic underpinnings underlying brain structural variation.


Asunto(s)
Encéfalo/anatomía & histología , Estudio de Asociación del Genoma Completo , Neuroimagen/tendencias , Encéfalo/diagnóstico por imagen , Pleiotropía Genética/genética , Humanos , Imagen por Resonancia Magnética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Tamaño de la Muestra
11.
Bioinformatics ; 35(1): 1-11, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29931045

RESUMEN

Motivation: Multiple marker analysis of the genome-wide association study (GWAS) data has gained ample attention in recent years. However, because of the ultra high-dimensionality of GWAS data, such analysis is challenging. Frequently used penalized regression methods often lead to large number of false positives, whereas Bayesian methods are computationally very expensive. Motivated to ameliorate these issues simultaneously, we consider the novel approach of using non-local priors in an iterative variable selection framework. Results: We develop a variable selection method, named, iterative non-local prior based selection for GWAS, or GWASinlps, that combines, in an iterative variable selection framework, the computational efficiency of the screen-and-select approach based on some association learning and the parsimonious uncertainty quantification provided by the use of non-local priors. The hallmark of our method is the introduction of 'structured screen-and-select' strategy, that considers hierarchical screening, which is not only based on response-predictor associations, but also based on response-response associations and concatenates variable selection within that hierarchy. Extensive simulation studies with single nucleotide polymorphisms having realistic linkage disequilibrium structures demonstrate the advantages of our computationally efficient method compared to several frequentist and Bayesian variable selection methods, in terms of true positive rate, false discovery rate, mean squared error and effect size estimation error. Further, we provide empirical power analysis useful for study design. Finally, a real GWAS data application was considered with human height as phenotype. Availability and implementation: An R-package for implementing the GWASinlps method is available at https://cran.r-project.org/web/packages/GWASinlps/index.html. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Programas Informáticos , Teorema de Bayes , Biología Computacional , Humanos , Análisis de Regresión
12.
Hepatology ; 70(1): 127-141, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30859582

RESUMEN

N-terminal propeptide of type 3 procollagen (PRO-C3) is a biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). This study examines the association between PRO-C3 concentration and liver fibrosis assessed by magnetic resonance elastography (MRE)-measured stiffness (MRE-stiffness) and the heritability of PRO-C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross-sectional analysis of a well-characterized prospective cohort of 306 participants, including 44 probands with NAFLD-cirrhosis and their 72 first-degree relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first-degree relatives, and 72 controls without NAFLD and their 72 first-degree relatives. Liver steatosis was assessed by magnetic resonance imaging proton density fat fraction, and liver fibrosis was assessed by MRE-stiffness. Serum PRO-C3 was assessed by competitive, enzyme-linked immunosorbent assay. We assessed the familial correlation of PRO-C3 concentration, the shared gene effects between PRO-C3 concentration and liver steatosis and fibrosis, and the association between PRO-C3 concentration and genetic variants in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing (MBOAT), and glucokinase regulator (CGKR) genes. In multivariable-adjusted models including age, sex, body mass index, and ethnicity, serum PRO-C3 correlated strongly with liver fibrosis (r2  = 0.50, P < 0.001) and demonstrated robust heritability (h2 , 0.36; 95% confidence interval [CI], 0.07, 0.59; P = 0.016). PRO-C3 concentration and steatosis had a strong genetic correlation (shared genetic determination: 0.62; 95% CI, 0.236, 1.001; P = 0.002), whereas PRO-C3 concentration and fibrosis had a strong environmental correlation (shared environmental determination: 0.55; 95% CI, 0.317, 0.717; P < 0.001). PRO-C3 concentrations were higher in carriers of the TM6SF2 rs58542926-T allele compared with noncarriers: 15.7 (± 10.5) versus 10.8 (± 5.7) ng/L (P = 0.047). Conclusion: Serum PRO-C3 correlates with MRE-assessed fibrosis, is heritable, shares genetic correlation with liver steatosis and shares environmental correlation with liver fibrosis. PRO-C3 concentration appears to be linked to both fibrosis and steatosis and increased in carriers of the TM6SF2 rs58542926 risk allele.


Asunto(s)
Colágeno Tipo III/sangre , Cirrosis Hepática/sangre , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto , Anciano , Diagnóstico por Imagen de Elasticidad , Estudios Epidemiológicos , Matriz Extracelular/metabolismo , Femenino , Humanos , Cirrosis Hepática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Carácter Cuantitativo Heredable
13.
Cerebellum ; 19(2): 217-225, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31900856

RESUMEN

Alzheimer's disease (AD) is a disease with dysfunctional brain network. Previous studies found the cerebellar volume changes over the course of AD disease progression; however, whether cerebellar volume change contributes to the cognitive decline in AD, or its earlier disease stage (i.e., mild cognitive impairment [MCI]) remains unclear. In ADNI, cognitive function was assessed using Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog). We used linear regression and linear mixed effects models to examine whether cerebellar volume is associated with either baseline cognition or with cognitive changes over time in MCI or in AD. We used logistic regression to assess the relationship between cerebellar volume and disease progression to MCI and AD. We found that cerebellar volume is associated with cognition in patients with MCI, after adjusting for age, gender, education, hippocampal volume, and APOE4 status. Consistently, cerebellar volume is associated with increased odds of the disease stages of MCI and AD when compared to controls. However, cerebellar volume is not associated with cognitive changes over time in either MCI or AD. In summary, cerebellar volume may contribute to cognition level in MCI, but not in AD, indicating that the cerebellar network might modulate the cognitive function in the early stage of the disease. The cerebellum may be a potential target for neuromodulation in treating MCI.


Asunto(s)
Cerebelo/patología , Disfunción Cognitiva/patología , Anciano , Anciano de 80 o más Años , Cognición/fisiología , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino
14.
Cereb Cortex ; 29(9): 3879-3890, 2019 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-30357317

RESUMEN

The human cerebral cortex is highly regionalized, and this feature emerges from morphometric gradients in the cerebral vesicles during embryonic development. We tested if this principle of regionalization could be traced from the embryonic development to the human life span. Data-driven fuzzy clustering was used to identify regions of coordinated longitudinal development of cortical surface area (SA) and thickness (CT) (n = 301, 4-12 years). The principal divide for the developmental SA clusters extended from the inferior-posterior to the superior-anterior cortex, corresponding to the major embryonic morphometric anterior-posterior (AP) gradient. Embryonic factors showing a clear AP gradient were identified, and we found significant differences in gene expression of these factors between the anterior and posterior clusters. Further, each identified developmental SA and CT clusters showed distinguishable life span trajectories in a larger longitudinal dataset (4-88 years, 1633 observations), and the SA and CT clusters showed differential relationships to cognitive functions. This means that regions that developed together in childhood also changed together throughout life, demonstrating continuity in regionalization of cortical changes. The AP divide in SA development also characterized genetic patterning obtained in an adult twin sample. In conclusion, the development of cortical regionalization is a continuous process from the embryonic stage throughout life.


Asunto(s)
Envejecimiento/fisiología , Corteza Cerebral/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Niño , Preescolar , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Adulto Joven
15.
Hum Mol Genet ; 26(22): 4530-4539, 2017 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-28973307

RESUMEN

Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective.


Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Modelos Genéticos , Trastornos Neuróticos/genética , Análisis de Secuencia de ADN/métodos , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Neuroticismo/fisiología , Polimorfismo de Nucleótido Simple
16.
Hepatology ; 68(3): 918-932, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29572891

RESUMEN

Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG :0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG :0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).


Asunto(s)
Microbioma Gastrointestinal , Cirrosis Hepática/sangre , Enfermedad del Hígado Graso no Alcohólico/sangre , Fenilpropionatos/sangre , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Cirrosis Hepática/microbiología , Masculino , Metformina , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/microbiología , Prueba de Estudio Conceptual
17.
PLoS Genet ; 12(1): e1005803, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26808560

RESUMEN

Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic ("z-score") of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a "relative enrichment score" for each SNP. For each stratum of these relative enrichment scores, we obtain nonparametric estimates of posterior expected test statistics and replication probabilities as a function of discovery z-scores, using a resampling-based approach that repeatedly and randomly partitions meta-analysis sub-studies into training and replication samples. We fit a scale mixture of two Gaussians model to each stratum, obtaining parameter estimates that minimize the sum of squared differences of the scale-mixture model with the stratified nonparametric estimates. We apply this approach to the recent genome-wide association study (GWAS) of SCZ (n = 82,315), obtaining a good fit between the model-based and observed effect sizes and replication probabilities. We observed that SNPs with low enrichment scores replicate with a lower probability than SNPs with high enrichment scores even when both they are genome-wide significant (p < 5x10-8). There were 693 and 219 independent loci with model-based replication rates ≥80% and ≥90%, respectively. Compared to analyses not incorporating relative enrichment scores, CM3 increased out-of-sample yield for SNPs that replicate at a given rate. This demonstrates that replication probabilities can be more accurately estimated using prior enrichment information with CM3.


Asunto(s)
Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Esquizofrenia/genética , Genómica , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple
18.
PLoS Genet ; 12(7): e1006143, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27459196

RESUMEN

The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10-3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets.


Asunto(s)
Corteza Cerebral/metabolismo , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/genética , Transcriptoma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Cadáver , Corteza Cerebral/anatomía & histología , Corteza Cerebral/diagnóstico por imagen , Niño , Preescolar , Femenino , Lóbulo Frontal/anatomía & histología , Lóbulo Frontal/diagnóstico por imagen , Perfilación de la Expresión Génica , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Fenotipo , Gemelos/genética
19.
Proc Natl Acad Sci U S A ; 112(50): 15462-7, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26575625

RESUMEN

There is a growing realization that early life influences have lasting impact on brain function and structure. Recent research has demonstrated that genetic relationships in adults can be used to parcellate the cortex into regions of maximal shared genetic influence, and a major hypothesis is that genetically programmed neurodevelopmental events cause a lasting impact on the organization of the cerebral cortex observable decades later. Here we tested how developmental and lifespan changes in cortical thickness fit the underlying genetic organizational principles of cortical thickness in a longitudinal sample of 974 participants between 4.1 and 88.5 y of age with a total of 1,633 scans, including 773 scans from children below 12 y. Genetic clustering of cortical thickness was based on an independent dataset of 406 adult twins. Developmental and adult age-related changes in cortical thickness followed closely the genetic organization of the cerebral cortex, with change rates varying as a function of genetic similarity between regions. Cortical regions with overlapping genetic architecture showed correlated developmental and adult age change trajectories and vice versa for regions with low genetic overlap. Thus, effects of genes on regional variations in cortical thickness in middle age can be traced to regional differences in neurodevelopmental change rates and extrapolated to further adult aging-related cortical thinning. This finding suggests that genetic factors contribute to cortical changes through life and calls for a lifespan perspective in research aimed at identifying the genetic and environmental determinants of cortical development and aging.


Asunto(s)
Envejecimiento/fisiología , Corteza Cerebral/anatomía & histología , Corteza Cerebral/crecimiento & desarrollo , Genes , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Peso al Nacer , Niño , Preescolar , Femenino , Humanos , Lactante , Longevidad , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto Joven
20.
PLoS Med ; 14(3): e1002258, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28323831

RESUMEN

BACKGROUND: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. METHODS AND FINDINGS: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. CONCLUSIONS: We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Apolipoproteínas E/genética , Evaluación Geriátrica/métodos , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteínas E/metabolismo , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiología
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