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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.
Artigo em Inglês | MEDLINE | ID: mdl-33887960

RESUMO

Background - The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease (ASCVD) is of fundamental importance given its global health and economic burden. Inhibition of angiopoietin-like 3 (ANGPTL3) has demonstrated a cardioprotective effect, showing promise for ASCVD treatment, and is currently the focus of ongoing clinical trials. Here we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. Methods - We assayed ANGPTL3 protein levels in ~1,000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. Results - In a variance components framework we identified that variation in ANGPTL3 was significantly heritable (h2=0.33, P=1.31×10-16). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (LOD = 6.18) to a locus on chromosome 1 at 90 cM, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss of function (LoF) variant, rs398122988 (N121Kfs*2), in ANGPTL3, that was significantly associated with lower ANGPTL3 levels (ß=-1.69 SDU, P=3.367×10-13), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. Conclusions - Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and LoF variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for ASCVD.

3.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805011

RESUMO

The in vitro modeling of cardiac development and cardiomyopathies in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) provides opportunities to aid the discovery of genetic, molecular, and developmental changes that are causal to, or influence, cardiomyopathies and related diseases. To better understand the functional and disease modeling potential of iPSC-differentiated CMs and to provide a proof of principle for large, epidemiological-scale disease gene discovery approaches into cardiomyopathies, well-characterized CMs, generated from validated iPSCs of 12 individuals who belong to four sibships, and one of whom reported a major adverse cardiac event (MACE), were analyzed by genome-wide mRNA sequencing. The generated CMs expressed CM-specific genes and were highly concordant in their total expressed transcriptome across the 12 samples (correlation coefficient at 95% CI =0.92 ± 0.02). The functional annotation and enrichment analysis of the 2116 genes that were significantly upregulated in CMs suggest that generated CMs have a transcriptomic and functional profile of immature atrial-like CMs; however, the CMs-upregulated transcriptome also showed high overlap and significant enrichment in primary cardiomyocyte (p-value = 4.36 × 10-9), primary heart tissue (p-value = 1.37 × 10-41) and cardiomyopathy (p-value = 1.13 × 10-21) associated gene sets. Modeling the effect of MACE in the generated CMs-upregulated transcriptome identified gene expression phenotypes consistent with the predisposition of the MACE-affected sibship to arrhythmia, prothrombotic, and atherosclerosis risk.

4.
Nat Commun ; 12(1): 2182, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846329

RESUMO

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.


Assuntos
Cromossomos Humanos X/genética , Lipídeos/sangue , Proteínas do Olho/metabolismo , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Fenômica , Polimorfismo de Nucleotídeo Único/genética , Tela Subcutânea/metabolismo , Sequenciamento Completo do Genoma
5.
Front Immunol ; 12: 630988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717164

RESUMO

Sea turtle fibropapillomatosis (FP) is a tumor promoting disease that is one of several threats globally to endangered sea turtle populations. The prevalence of FP is highest in green sea turtle (Chelonia mydas) populations, and historically has shown considerable temporal growth. FP tumors can significantly affect the ability of turtles to forage for food and avoid predation and can grow to debilitating sizes. In the current study, based in South Texas, we have applied transcriptome sequencing to FP tumors and healthy control tissue to study the gene expression profiles of FP. By identifying differentially expressed turtle genes in FP, and matching these genes to their closest human ortholog we draw on the wealth of human based knowledge, specifically human cancer, to identify new insights into the biology of sea turtle FP. We show that several genes aberrantly expressed in FP tumors have known tumor promoting biology in humans, including CTHRC1 and NLRC5, and provide support that disruption of the Wnt signaling pathway is a feature of FP. Further, we profiled the expression of current targets of immune checkpoint inhibitors from human oncology in FP tumors and identified potential candidates for future studies.

6.
Genetics ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720349

RESUMO

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence datasets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently amongst the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

7.
Transl Psychiatry ; 11(1): 182, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753722

RESUMO

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

8.
Eur Psychiatry ; 64(1): e29, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33785081

RESUMO

BACKGROUND: Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation. METHODS: Using data from 9,421 individuals aged 8-21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation. RESULTS: Externalizing was heritable (h2 = 0.46, p = 1 × 10-6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = -0.412, p = 0.004), verbal reasoning (ρg = -0.485, p = 0.001), spatial reasoning (ρg = -0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10-4), verbal knowledge (ρg = -0.314, p = 0.002), and general cognitive ability (g)(ρg = -0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = -0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing. CONCLUSIONS: Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.

9.
Methods Mol Biol ; 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33772461

RESUMO

In vitro hepatocyte cell models are being used to study the pathogenesis of liver disease and in the discovery and preclinical stages of drug development. The culture of hepatic cell lines and primary hepatocytes as in vitro cell models has been carried out for several decades. However, hepatic cell lines (hepatic carcinoma generated or immortalized) have limited accuracy when recapitulating complex physiological functions of the liver. Additionally, primary hepatocytes sourced from human cadavers or medical biopsies are difficult to obtain due to sourcing limitations, particularly for large-scale population studies or in applications requiring large number of cells. Hepatocyte cultures differentiated from human embryonic stem cells (ESCs) and induced pluripotent stem cell (iPSCs) overcome in large part the limitations of traditional hepatocyte in vitro models. In this chapter, we described an efficient protocol routinely used in our laboratory to differentiate human iPSCs into functional hepatocyte cultures for in vitro modeling of liver function and disease. The protocol uses a three-stage differentiation strategy to generate functional hepatocytes from human iPSCs. The differentiated cells show characteristic hepatocyte morphology including flat and polygonal shape, distinct round nuclei, and presence of biliary canaliculi and they express hepatic markers alpha-fetoprotein (AFP), albumin (ALB), E-cadherin (CHD1), hepatocyte nuclear factor 4 alpha (HNF4α), and actin.

10.
Nature ; 590(7845): 290-299, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568819

RESUMO

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Genômica , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisão , Citocromo P-450 CYP2D6/genética , Haplótipos/genética , Heterozigoto , Humanos , Mutação INDEL , Mutação com Perda de Função , Mutagênese , Fenótipo , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Medicina de Precisão/normas , Controle de Qualidade , Tamanho da Amostra , Estados Unidos , Sequenciamento Completo do Genoma/normas
11.
Sci Rep ; 11(1): 871, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441626

RESUMO

High concentrations of carotenoids are protective against cardiometabolic risk traits (CMTs) in adults and children. We recently showed in non-diabetic Mexican American (MA) children that serum α-carotene and ß-carotene are inversely correlated with obesity measures and triglycerides and positively with HDL cholesterol and that they were under strong genetic influences. Additionally, we previously described a Pediatric Metabolic Index (PMI) that helps in the identification of children who are at risk for cardiometabolic diseases. Here, we quantified serum lycopene and ß-cryptoxanthin concentrations in approximately 580 children from MA families using an ultraperformance liquid chromatography-photodiode array and determined their heritabilities and correlations with CMTs. Using response surface methodology (RSM), we determined two-way interactions of carotenoids and PMI on Matsuda insulin sensitivity index (ISI). The concentrations of lycopene and ß-cryptoxanthin were highly heritable [h2 = 0.98, P = 7 × 10-18 and h2 = 0.58, P = 1 × 10-7]. We found significant (P ≤ 0.05) negative phenotypic correlations between ß-cryptoxanthin and five CMTs: body mass index (- 0.22), waist circumference (- 0.25), triglycerides (- 0.18), fat mass (- 0.23), fasting glucose (- 0.09), and positive correlations with HDL cholesterol (0.29). In contrast, lycopene only showed a significant negative correlation with fasting glucose (- 0.08) and a positive correlation with HDL cholesterol (0.18). Importantly, we found that common genetic influences significantly contributed to the observed phenotypic correlations. RSM showed that increased serum concentrations of α- and ß-carotenoids rather than that of ß-cryptoxanthin or lycopene had maximal effects on ISI. In summary, our findings suggest that the serum carotenoids are under strong additive genetic influences and may have differential effects on susceptibility to CMTs in children.

12.
Sci Rep ; 11(1): 1932, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479282

RESUMO

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m-2) or obese (BMI ≥ 30 kg m-2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.

13.
Hum Brain Mapp ; 42(6): 1727-1741, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33340172

RESUMO

Although previous studies have highlighted associations of cannabis use with cognition and brain morphometry, critical questions remain with regard to the association between cannabis use and brain structural and functional connectivity. In a cross-sectional community sample of 205 African Americans (age 18-70) we tested for associations of cannabis use disorder (CUD, n = 57) with multi-domain cognitive measures and structural, diffusion, and resting state brain-imaging phenotypes. Post hoc model evidence was computed with Bayes factors (BF) and posterior probabilities of association (PPA) to account for multiple testing. General cognitive functioning, verbal intelligence, verbal memory, working memory, and motor speed were lower in the CUD group compared with non-users (p < .011; 1.9 < BF < 3,217). CUD was associated with altered functional connectivity in a network comprising the motor-hand region in the superior parietal gyri and the anterior insula (p < .04). These differences were not explained by alcohol, other drug use, or education. No associations with CUD were observed in cortical thickness, cortical surface area, subcortical or cerebellar volumes (0.12 < BF < 1.5), or graph-theoretical metrics of resting state connectivity (PPA < 0.01). In a large sample collected irrespective of cannabis used to minimize recruitment bias, we confirm the literature on poorer cognitive functioning in CUD, and an absence of volumetric brain differences between CUD and non-CUD. We did not find evidence for or against a disruption of structural connectivity, whereas we did find localized resting state functional dysconnectivity in CUD. There was sufficient proof, however, that organization of functional connectivity as determined via graph metrics does not differ between CUD and non-user group.

14.
Cerebellum ; 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33159660

RESUMO

The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Hum Brain Mapp 40(12):3575-3588, 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post hoc analyses using T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) in the form of voxel-wise tract-based spatial statistics (TBSS), biometric, and psychometric data from young participants with (n = 52, aged 18-35 years) and without MetS (n = 52, aged 18-35 years). To test the predictive value of components of the Schmahmann syndrome scale (SSS), also known as the cerebellar cognitive affective syndrome scale, we used structural equation modeling to adapt available psychometric scores in our participant sample to the SSS and compare them to the composite score of all psychometric data available. Our key findings point to a statistically significant correlation between TBSS fractional anisotropy (FA) values from DTI and adapted SSS psychometric scores in individuals with MetS (r2 = .139, 95% CI = 0.009, .345). This suggests that the SSS could be applied to assess cognitive and likely neuroanatomical effects associated with MetS. We strongly suggest that future work aimed at investigating the neurocognitive effects of MetS and related comorbidities (i.e., dyslipidemia, diabetes, obesity) would benefit from implementing and further exploring the validity of the SSS in this patient population.

15.
PLoS One ; 15(10): e0240467, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33057385

RESUMO

AIM: Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs). METHODS: We used data from 670 non-diabetic MA children, aged 6-17 years (49% girls). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes. RESULTS: Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q. CONCLUSION: Our study suggests that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children.

16.
Int J Mol Sci ; 21(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977388

RESUMO

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA-mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change-absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10-15-1.44 × 10-4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.

17.
Commun Biol ; 3(1): 510, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934300

RESUMO

Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be reliably extracted from in-vivo MRI must be established. Using four independent test-retest datasets, we found high reliability across the brain (intraclass correlation interquartile range: 0.65-0.85). Heritability estimates were derived for three family-based cohorts using variance components analysis and pooled (total N > 3000); the overall sulcal heritability pattern was correlated to that derived for a large population cohort (N > 9000) calculated using genomic complex trait analysis. Overall, sulcal width was the most heritable metric, and earlier forming sulci showed higher heritability. The inter-hemispheric genetic correlations were high, yet select sulci showed incomplete pleiotropy, suggesting hemisphere-specific genetic influences.

18.
Nat Genet ; 52(9): 969-983, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839606

RESUMO

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Genoma/genética , LDL-Colesterol/genética , Simulação por Computador , Estudo de Associação Genômica Ampla/métodos , Humanos , Modelos Genéticos , Anotação de Sequência Molecular/métodos , Fenótipo , Sequenciamento Completo do Genoma/métodos
19.
Schizophr Bull ; 2020 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-32681179

RESUMO

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter "regional vulnerability index" (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen's d = 0.44, P = 1·10-5, N = 173 patients/230 control) and replication (Cohen's d = 0.78, P = 9·10-7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.

20.
Cereb Cortex ; 30(9): 5014-5027, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32377664

RESUMO

In recent years, replicability of neuroscientific findings, specifically those concerning correlates of morphological properties of gray matter (GM), have been subject of major scrutiny. Use of different processing pipelines and differences in their estimates of the macroscale GM may play an important role in this context. To address this issue, here, we investigated the cortical thickness estimates of three widely used pipelines. Based on analyses in two independent large-scale cohorts, we report high levels of within-pipeline reliability of the absolute cortical thickness-estimates and comparable spatial patterns of cortical thickness-estimates across all pipelines. Within each individual, absolute regional thickness differed between pipelines, indicating that in-vivo thickness measurements are only a proxy of actual thickness of the cortex, which shall only be compared within the same software package and thickness estimation technique. However, at group level, cortical thickness-estimates correlated strongly between pipelines, in most brain regions. The smallest between-pipeline correlations were observed in para-limbic areas and insula. These regions also demonstrated the highest interindividual variability and the lowest reliability of cortical thickness-estimates within each pipeline, suggesting that structural variations within these regions should be interpreted with caution.

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