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1.
Mov Disord ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34612543

RESUMO

BACKGROUND: Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders. OBJECTIVES: We aimed to develop and validate a polygenic hazard score model in sporadic PD. METHODS: Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls. RESULTS: A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49-4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. CONCLUSIONS: We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

2.
Chembiochem ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606179

RESUMO

The imaging of peptidoglycan (PGN) dynamics in living bacteria facilitates the understanding of PGN biosynthesis and wall-targeting antibiotics. The main tools for imaging bacterial PGN are fluorescent probes, such as well-discussed PGN metabolic labeling probes. However, the fluorescent small-molecule probes for labeling key PGN-synthesizing enzymes, especially for transglycosylases (TGases), remain to be explored. In this work, the first imaging probe labeling TGase in bacterial cell wall studies was reported. We synthesized various fluorescent MoeA-based molecules by derivatizing the natural antibiotic moenomycin A (MoeA), and used them to label TGases in living bacteria, monitor bacterial growth and division cycles by time-lapse imaging, and study cell wall growth in the mecA-carrying Methicillin-Resistant S. aureus (MRSA) strains when the ß-lactam-based probes were unsuitable.

3.
Molecules ; 26(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34641483

RESUMO

A phytochemical investigation on the roots of medicinal plant Eurycoma longifolia resulted in the isolation of 10 new highly oxygenated C20 quassinoids longifolactones G‒P (1-10), along with four known ones (11-14). Their chemical structures and absolute configurations were unambiguously elucidated on the basis of comprehensive spectroscopic analysis and X-ray crystallographic data. Notably, compound 1 is a rare pentacyclic C20 quassinoid featuring a densely functionalized 2,5-dioxatricyclo[5.2.2.04,8]undecane core. Compound 4 represents the first example of quassinoids containing a 14,15-epoxy functionality, and 7 features an unusual α-oriented hydroxyl group at C-14. All isolated compounds were evaluated for their anti-proliferation activities on human leukemia cells. Among the isolates, compounds 5, 12, 13, and 14 potently inhibited the in vitro proliferation of K562 and HL-60 cells with IC50 values ranging from 2.90 to 8.20 µM.

4.
Arterioscler Thromb Vasc Biol ; : ATVBAHA121316867, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34551592

RESUMO

OBJECTIVE: Angiogenic factor AGGF1 (angiogenic factor and G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified α5ß1 as the receptor for AGGF1 on ECs. AGGF1 interacts with α5ß1 and activates FAK (focal adhesion kinase), Src, and AKT. Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from -RDD- to -RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. CONCLUSIONS: We have identified integrin α5ß1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of α5ß1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with α5ß1 and signaling.

5.
Transl Psychiatry ; 11(1): 466, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497263

RESUMO

Increased risk-taking is a central component of bipolar disorder (BIP) and is implicated in schizophrenia (SCZ). Risky behaviours, including smoking and alcohol use, are overrepresented in both disorders and associated with poor health outcomes. Positive genetic correlations are reported but an improved understanding of the shared genetic architecture between risk phenotypes and psychiatric disorders may provide insights into underlying neurobiological mechanisms. We aimed to characterise the genetic overlap between risk phenotypes and SCZ, and BIP by estimating the total number of shared variants using the bivariate causal mixture model and identifying shared genomic loci using the conjunctional false discovery rate method. Summary statistics from genome wide association studies of SCZ, BIP, risk-taking and risky behaviours were acquired (n = 82,315-466,751). Genomic loci were functionally annotated using FUMA. Of 8.6-8.7 K variants predicted to influence BIP, 6.6 K and 7.4 K were predicted to influence risk-taking and risky behaviours, respectively. Similarly, of 10.2-10.3 K variants influencing SCZ, 9.6 and 8.8 K were predicted to influence risk-taking and risky behaviours, respectively. We identified 192 loci jointly associated with SCZ and risk phenotypes and 206 associated with BIP and risk phenotypes, of which 68 were common to both risk-taking and risky behaviours and 124 were novel to SCZ or BIP. Functional annotation implicated differential expression in multiple cortical and sub-cortical regions. In conclusion, we report extensive polygenic overlap between risk phenotypes and BIP and SCZ, identify specific loci contributing to this shared risk and highlight biologically plausible mechanisms that may underlie risk-taking in severe psychiatric disorders.


Assuntos
Transtorno Bipolar , Esquizofrenia , Transtorno Bipolar/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Esquizofrenia/genética
7.
Ecotoxicol Environ Saf ; 225: 112767, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34507039

RESUMO

Serious hexavalent chromium [Cr(VI)] pollution has continuously threatened ecological security and public health. Microorganism-assisted remediation technology has strong potential in the treatment of environmental Cr(VI) pollution due to its advantages of high efficiency, low cost, and low secondary pollution. Sporosarcina saromensis M52, a strain with strong Cr(VI) removal ability, isolated from coastal intertidal zone was used in this study. Scanning electron microscopy coupled with energy dispersive X-ray analysis indicated M52 was relatively stable under Cr(VI) stress and trace amount of Cr deposited on the cell surface. X-ray photoelectron spectroscopy and X-ray diffraction analyses exhibited M52 could reduce Cr(VI) into Cr(III). Fourier transform infrared spectroscopy showed the bacterial surface was mainly consisted of polysaccharides, phosphate groups, carboxyl groups, amide II (NH/CN) groups, alkyl groups, and hydroxyl groups, while functional groups involving in Cr(VI) bio-reduction were not detected. According to these characterization analyses, the removal of Cr(VI) was primarily depended on bio-reduction, instead of bio-adsorption by M52. Genome analyses further indicated the probable mechanisms of bio-reduction, including the active efflux of Cr(VI) by chromate transporter ChrA, enzymatic redox reactions mediated by reductases, DNA-repaired proteases ability to minimize the ROS damage, and the formation of specific cell components to minimize the biofilm injuries caused by Cr(VI). These studies provided a theoretical basis which was useful for Cr(VI) remediation, especially in terms of increasing its effectiveness. THE MAIN FINDING OF THE WORK: M52 realized the bioremediation of Cr(VI) majorly through bio-reduction, including Cr(VI) efflux, chromate reduction, DNA repair, and the formation of specific cell components, instead of bio-adsorption.


Assuntos
Genômica , Sporosarcina , Cromo , Sporosarcina/genética
8.
Chin J Integr Med ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581940

RESUMO

OBJECTIVE: To reveal the neuroprotective effect and the underlying mechanisms of a mixture of the main components of Panax notoginseng saponins (TSPN) on cerebral ischemia-reperfusion injury and oxygen-glucose deprivation/reoxygenation (OGD/R) of cultured cortical neurons. METHODS: The neuroprotective effect of TSPN was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and live/dead cell assays. The morphology of dendrites was detected by immunofluorescence. Middle cerebral artery occlusion (MCAO) was developed in rats as a model of cerebral ischemia-reperfusion. The neuroprotective effect of TSPN was evaluated by neurological scoring, tail suspension test, 2,3,5-triphenyltetrazolium chloride (TTC) and Nissl stainings. Western blot analysis, immunohistochemistry and immunofluorescence were used to measure the changes in the Akt/mammalian target of rapamycin (mTOR) signaling pathway. RESULTS: MTT showed that TSPN (50, 25 and 12.5 µ g/mL) protected cortical neurons after OGD/R treatment (P<0.01 or P<0.05). Flow cytometry and live/dead cell assays indicated that 25 µ g/mL TSPN decreased neuronal apoptosis (P<0.05), and immunofluorescence showed that 25 µ g/mL TSPN restored the dendritic morphology of damaged neurons (P<0.05). Moreover, 12.5 µ g/mL TSPN downregulated the expression of Beclin-1, Cleaved-caspase 3 and LC3B-II/LC3B-I, and upregulated the levels of phosphorylated (p)-Akt and p-mTOR (P<0.01 or P<0.05). In the MCAO model, 50 µ g/mL TSPN improved defective neurological behavior and reduced infarct volume (P<0.05). Moreover, the expression of Beclin-1 and LC3B in cerebral ischemic penumbra was downregulated after 50 µ g/mL TSPN treatment, whereas the p-mTOR level was upregulated (P<0.05 or P<0.01). CONCLUSION: TSPN promoted neuronal survival and protected dendrite integrity after OGD/R and had a potential therapeutic effect by alleviating neurological deficits and reversing neuronal loss. TSPN promoted p-mTOR and inhibited Beclin-1 to alleviate ischemic damage, which may be the mechanism that underlies the neuroprotective activity of TSPN.

9.
Bioorg Chem ; 116: 105337, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34521046

RESUMO

A phytochemical investigation on the alkaloids from water-soluble part of Sophora alopecuroides led to obtain forty matrine-type alkaloids (1-40) including eighteen new ones (1-18), which covers almost all positions of the oxygen substitution in matrine-type structure. Notably, eight compounds (1-8) belong to rare bis-amide matrine-type alkaloid. The new structures were determined based on extensive spectroscopic data, electronic circular dichroism (ECD) calculations, and six instances, verified by X-ray crystallography. Most of isolates showed anti-neuroinflammatory activities based on the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in BV2 microglia cells. Especially, compound 39 can suppress those two mediator secretions in a dose-dependent manner with IC50 values of 21.6 ± 0.5 and 16.7 ± 0.8 µM, respectively. Further mechanistic study revealed that 39 suppressed the phosphorylation of IκBα and p65 subunit to regulate the NF-κB signaling pathway.

10.
Mayo Clin Proc ; 96(10): 2528-2539, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34538426

RESUMO

OBJECTIVE: To identify risk factors associated with severe COVID-19 infection in a defined Midwestern US population overall and within different age groups. PATIENTS AND METHODS: We used the Rochester Epidemiology Project research infrastructure to identify persons residing in a defined 27-county Midwestern region who had positive results on polymerase chain reaction tests for COVID-19 between March 1, 2020, and September 30, 2020 (N=9928). Age, sex, race, ethnicity, body mass index, smoking status, and 44 chronic disease categories were considered as possible risk factors for severe infection. Severe infection was defined as hospitalization or death caused by COVID-19. Associations between risk factors and severe infection were estimated using Cox proportional hazard models overall and within 3 age groups (0 to 44, 45 to 64, and 65+ years). RESULTS: Overall, 474 (4.8%) persons developed severe COVID-19 infection. Older age, male sex, non-White race, Hispanic ethnicity, obesity, and a higher number of chronic conditions were associated with increased risk of severe infection. After adjustment, 36 chronic disease categories were significantly associated with severe infection. The risk of severe infection varied significantly across age groups. In particular, persons 0 to 44 years of age with cancer, chronic neurologic disorders, hematologic disorders, ischemic heart disease, and other endocrine disorders had a greater than 3-fold increased risk of severe infection compared with persons of the same age without those conditions. Associations were attenuated in older age groups. CONCLUSION: Older persons are more likely to experience severe infections; however, severe cases occur in younger persons as well. Our data provide insight regarding younger persons at especially high risk of severe COVID-19 infection.

11.
Nat Prod Res ; : 1-7, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507510

RESUMO

Bixasteroid (1), one new steroid together with five known compounds (2-6), were isolated from the ethyl acetate fraction of ethanol extract of Bixa orellana fruits. All of these known compounds were isolated from the plant for the first time. Their structures were elucidated on the basis of spectroscopic analysis, and the absolute configuration of compound 1 was determined by X-ray crystallographic data analysis as well as by the quantum chemical ECD calculations. All the isolated compounds were tested for their anti-inflammatory activities. Compounds 1 and 2 showed inhibiting NO release activities in LPS-induced RAW 264.7 macrophages with the IC50 values of 4.72 ± 0.28 and 5.48 ± 1.48 µM, respectively.

12.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3123-3132, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467704

RESUMO

The chemical constituents from the leaves of Ilex guayusa were investigated. Sixteen triterpenoids were isolated from the 95% ethanol extract of dried leaves of I. guayusa by silica gel, Sephadex LH-20, and ODS column chromatographies and semi-prepa-rative HPLC. Those triterpenoids were identified by NMR, HR-MS, and literature analysis: 3ß-hydroxy-11α,12α-epoxy-24-nor-urs-4(23)-ene-28,13ß-olide(1), 3ß-hydroxy-24-nor-4(23),12-oleanadien-28-methyl ester(2), oleanolic acid(3), 3ß,28-dihydroxy-12-oleanene(4), 2α,3ß-dihydroxy-11α,12α-epoxy-24-'nor-olean-4(23)-ene-28,13ß-olide(5), ursolic acid(6), 3ß,23-dihydroxy ursolic acid(7), 3ß,28-dihydroxy-12-ursene(8), 3ß-28-nor-urs-12-ene-3,17-diol(9), 3ß-hydroxyurs-11-ene-28,13ß-olide(10), 13ß,28-epoxy-3ß-hydroxy-11-ursene(11), 3ß-hydroxy-28,28-dimethoxy-12-ursene(12), 3ß-hydroxy-24-nor-urs-4(23),12-dien-28-oic acid(13), 3ß-hydroxy-24-nor-urs-4(23),12-dien-28-methyl ester(14), 2α,3ß-dihydroxy-11α,12α-epoxy-24-nor-urs-4(23)-ene-28,13ß-olide(15) and 2α,3ß-dihydroxy-11α,12α-epoxy-24-nor-urs-4(23),20(30)-dien-28,13ß-olide(16). Compounds 1-2 were new compounds, and compounds 4-5, 7 and 9-16 were isolated from I. guayusa for the first time.


Assuntos
Medicamentos de Ervas Chinesas , Ilex guayusa , Ácido Oleanólico , Triterpenos , Estrutura Molecular , Folhas de Planta
14.
Neuroimage ; 244: 118603, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34560273

RESUMO

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study®. This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.

15.
BMC Immunol ; 22(1): 54, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380427

RESUMO

BACKGROUND: Both hepatitis C virus (HCV) infection and adiponectin are critically involved in metabolism. The reversal and associations of altering adiponectin levels after sustained virological responses (SVRs) following direct-acting antivirals (DAA) in HCV-infected patients remained elusive. METHODS: A joint study was conducted in a prospective cohort of 427 HCV-infected patients and a line of HCV core transgenic mice. RESULTS: Of 427, 358 had completed a course of DAA therapy and 353 had SVRs. At baseline, male sex (95% CI ß: - 1.44 to - 0.417), estimated glomerular filtration rate (eGFR) (- 0.025 to - 0.008), triglycerides (- 0.015 to - 0.005), and fibrosis-4 levels (0.08-0.297) were associated with adiponectin levels; BMI (0.029-0.327) and triglycerides levels (0.01-0.03) were associated with homeostatic model assessment for insulin resistance (HOMA-IR) in HCV-infected patients. At 24-week post-therapy, in SVR patients, male sex (- 1.89 to - 0.5) and eGFR (- 0.02 to - 0.001) levels were associated with adiponectin levels, levels of BMI (0.094-0.335) and alanine transaminase (0.018-0.078) were associated with HOMA-IR; compared with baseline levels, adiponectin levels decreased (6.53 ± 2.77 vs. 5.45 ± 2.56 µg/mL, p < 0.001). In 12-month-old HCV core transgenic mice with hepatic steatosis, triglyceride levels (0.021-0.111) were associated with adiponectin levels, and hepatic adipopnectin expression was comparable with that of control mice. CONCLUSIONS: Triglycerides and hepatic fibrosis are associated with HCV-specific alteration of adiponectin levels, and adiponectin may affect insulin sensitivity through triglycerides during HCV infection. In DAA-treated patients, after SVR, adiponectin levels decreased and the linking function of triglycerides between adiponectin and insulin sensitivity vanished. Moreover, HCV core with hepatic steatosis might affect extrahepatic adiponectin expression through triglycerides.

16.
Zhongguo Zhong Yao Za Zhi ; 46(13): 3364-3367, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34396756

RESUMO

Mansoa alliacea,commonly known as garlic vine,is native to the tropical rain forests of South America and widely cultivated in South China. As a popular folk medicine with various biological activities,however,this plant remains to be fully elucidated in terms of its phytochemical constituents. In this study,two new pyranonaphthoquinones were isolated from the 95% ethanol extract of the leaves and twigs of M. alliacea by various chromatographic approaches including silica gel,octadecyl silica( ODS),Sephadex LH-20,and preparative high-performance liquid chromatography( PHPLC). Their structures were determined to be 8,9-dimethoxy-α-lapachone( 1) and 7-hydroxy-8,9-dimethoxy-α-lapachone( 2) by comprehensive spectroscopic analyses and therefore respectively named as mansonin A( 1) and mansonin B( 2).


Assuntos
Compostos Fitoquímicos , Folhas de Planta , China , Cromatografia Líquida de Alta Pressão
17.
Neurobiol Aging ; 107: 70-77, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34399127

RESUMO

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.

18.
Sci Rep ; 11(1): 14617, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272416

RESUMO

The etiology of Kawasaki Disease (KD), the most common cause of acquired heart disease in children in developed countries, remains elusive, but could be multifactorial in nature as suggested by the numerous environmental and infectious exposures that have previously been linked to its epidemiology. There is still a lack of a comprehensive model describing these complex associations. We present a Bayesian disease model that provides insight in the spatiotemporal distribution of KD in Canada from 2004 to 2017. The disease model including environmental factors had improved Watanabe-Akaike information criterion (WAIC) compared to the base model which included only spatiotemporal and demographic effects and had excellent performance in recapitulating the spatiotemporal distribution of KD in Canada (98% and 86% spatial and temporal correlations, respectively). The model suggests an association between the distribution of KD and population composition, weather-related factors, aeroallergen exposure, pollution, atmospheric concentration of spores and algae, and the incidence of healthcare encounters for bacterial pneumonia or viral intestinal infections. This model could be the basis of a hypothetical data-driven framework for the spatiotemporal distribution of KD. It also generates novel hypotheses about the etiology of KD, and provides a basis for the future development of a predictive and surveillance model.

19.
Org Lett ; 23(15): 5885-5890, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34279973

RESUMO

A new tandem annulation of p-quinone methides (p-QMs) with ynamides is described. This cascade reaction features a unique combination of (2 + 2) annulation, retro-4π electrocyclization, and imino-Nazarov cyclization, wherein vinyl p-quinone methides (p-VQMs) as one of the key intermediates have been identified chemically. Significantly, an unusual structural reconstruction of p-QMs involving the cleavage of the C5-C6 bond and the late-stage formation of the C4-C6 bond is involved, leading to a methodology development for the construction of functionalized aminoindenes.

20.
Brain ; 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273149

RESUMO

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression, and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases=59,674; n controls=316,078), bipolar disorder (n cases=20,352; n controls=31,358), depression (n cases=170,756; n controls=328,443) and schizophrenia (n cases=40,675, n controls=64,643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterised to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8K disorder-influencing variants) compared to mental disorders (8.1K-12.3K disorder-influencing variants). Bivariate analysis estimated that 0.8K (0.3K), 2.1K (SD = 0.1K) and 2.3K (SD = 0.3K) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1.8K, SD = 0.3K) and educational attainment (2.1K, SD = 0.3K) but not height (1K, SD = 0.1K). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2, SLC9B1. Gene-set analysis identified several putative gene-sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants which influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

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