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Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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Apolipoproteínas E , Demencia Frontotemporal , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas tau , Humanos , Demencia Frontotemporal/genética , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Femenino , Anciano , Polimorfismo de Nucleótido Simple , Sitios Genéticos , Persona de Mediana Edad , Estudios de Casos y Controles , Proteínas de la MielinaRESUMEN
Genome-wide association studies (GWAS) implicate broad genomic loci containing clusters of highly correlated genetic variants. Finemapping techniques can select and prioritize variants within each GWAS locus which are more likely to have a functional influence on the trait. Here, we present a novel method, Finemap-MiXeR, for finemapping causal variants from GWAS summary statistics, controlling for correlation among variants due to linkage disequilibrium. Our method is based on a variational Bayesian approach and direct optimization of the Evidence Lower Bound (ELBO) of the likelihood function derived from the MiXeR model. After obtaining the analytical expression for ELBO's gradient, we apply Adaptive Moment Estimation (ADAM) algorithm for optimization, allowing us to obtain the posterior causal probability of each variant. Using these posterior causal probabilities, we validated Finemap-MiXeR across a wide range of scenarios using both synthetic data, and real data on height from the UK Biobank. Comparison of Finemap-MiXeR with two existing methods, FINEMAP and SuSiE RSS, demonstrated similar or improved accuracy. Furthermore, our method is computationally efficient in several aspects. For example, unlike many other methods in the literature, its computational complexity does not increase with the number of true causal variants in a locus and it does not require any matrix inversion operation. The mathematical framework of Finemap-MiXeR is flexible and may also be applied to other problems including cross-trait and cross-ancestry finemapping.
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Algoritmos , Teorema de Bayes , Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Estudio de Asociación del Genoma Completo/métodos , Humanos , Polimorfismo de Nucleótido Simple/genética , Modelos Genéticos , Sitios de Carácter CuantitativoRESUMEN
Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.
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Plasticidad Neuronal , Esquizofrenia , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Esquizofrenia/metabolismo , Humanos , Plasticidad Neuronal/genética , Simulación por Computador , Potenciación a Largo Plazo/genética , Receptores AMPA/genética , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Sinapsis/genética , Electroencefalografía , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Modelos Neurológicos , Depresión Sináptica a Largo Plazo/genética , Masculino , Potenciales Evocados Visuales/fisiologíaRESUMEN
TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.
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Neocórtex , Animales , Humanos , Ratones , Células Ependimogliales , Ratones NoqueadosRESUMEN
Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
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Esquizofrenia , Masculino , Femenino , Humanos , Esquizofrenia/diagnóstico por imagen , Estudios de Casos y Controles , Encéfalo/diagnóstico por imagen , Corteza Cerebral , Imagen por Resonancia Magnética/métodos , Lateralidad FuncionalRESUMEN
The occurrence of immune disease comorbidities in Alzheimer's disease (AD) has been observed in both epidemiological and molecular studies, suggesting a neuroinflammatory basis in AD. However, their shared genetic components have not been systematically studied. Here, we composed an atlas of the shared genetic associations between 11 immune-mediated diseases and AD by analyzing genome-wide association studies (GWAS) summary statistics. Our results unveiled a significant genetic overlap between AD and 11 individual immune-mediated diseases despite negligible genetic correlations, suggesting a complex shared genetic architecture distributed across the genome. The shared loci between AD and immune-mediated diseases implicated several genes, including GRAMD1B, FUT2, ADAMTS4, HBEGF, WNT3, TSPAN14, DHODH, ABCB9, and TNIP1, all of which are protein-coding genes and thus potential drug targets. Top biological pathways enriched with these identified shared genes were related to the immune system and cell adhesion. In addition, in silico single-cell analyses showed enrichment of immune and brain cells, including neurons and microglia. In summary, our results suggest a genetic relationship between AD and the 11 immune-mediated diseases, pinpointing the existence of a shared however non-causal genetic basis. These identified protein-coding genes have the potential to serve as a novel path to therapeutic interventions for both AD and immune-mediated diseases and their comorbidities.
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Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n = 989, female n = 530) and 1723 controls (male n = 997, female n = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.
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The aetiology of conduct problems involves a combination of genetic and environmental factors, many of which are inherently linked to parental characteristics given parents' central role in children's lives across development. It is important to disentangle to what extent links between parental heritable characteristics and children's behaviour are due to transmission of genetic risk or due to parental indirect genetic influences via the environment (i.e., genetic nurture). We used 31,290 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Maternal or self-reports of conduct problems at ages 8 and 14 years were available for up to 15,477 children. We found significant genetic transmission effects on conduct problems for 12 out of 13 PGS at age 8 years (strongest association: PGS for smoking, ß = 0.07, 95% confidence interval = [0.05, 0.08]) and for 4 out of 13 PGS at age 14 years (strongest association: PGS for externalising problems, ß = 0.08, 95% confidence interval = [0.05, 0.11]). Conversely, we did not find genetic nurture effects for conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics and child conduct problems. Our results may also indicate that genetic nurture via traits indexed by our polygenic scores is of limited aetiological importance for conduct problems-though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility.
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Trastorno de la Conducta , Herencia Multifactorial , Humanos , Femenino , Niño , Noruega , Masculino , Adolescente , Factores de Riesgo , Herencia Multifactorial/genética , Estudios de Cohortes , Trastorno de la Conducta/genética , Trastorno de la Conducta/epidemiología , Adulto , Madres , Padre , Problema de Conducta , Predisposición Genética a la Enfermedad/genética , GenotipoRESUMEN
Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.
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Encéfalo , Aprendizaje Automático , Imagen por Resonancia Magnética , Neuroimagen , Trastornos Psicóticos , Humanos , Trastornos Psicóticos/patología , Trastornos Psicóticos/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Masculino , Femenino , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Adulto , Adulto Joven , Adolescente , Síntomas ProdrómicosRESUMEN
Parkinson's disease is an age-related neurodegenerative disorder with a higher incidence in males than females. The causes for this sex difference are unknown. Genome-wide association studies (GWAS) have identified 90 Parkinson's disease risk loci, but the genetic studies have not found sex-specific differences in allele frequency on autosomal chromosomes or sex chromosomes. Genetic variants, however, could exert sex-specific effects on gene function and regulation of gene expression. To identify genetic loci that might have sex-specific effects, we studied pleiotropy between Parkinson's disease and sex-specific traits. Summary statistics from GWASs were acquired from large-scale consortia for Parkinson's disease (n cases = 13 708; n controls = 95 282), age at menarche (n = 368 888 females) and age at menopause (n = 69 360 females). We applied the conditional/conjunctional false discovery rate (FDR) method to identify shared loci between Parkinson's disease and these sex-specific traits. Next, we investigated sex-specific gene expression differences in the superior frontal cortex of both neuropathologically healthy individuals and Parkinson's disease patients (n cases = 61; n controls = 23). To provide biological insights to the genetic pleiotropy, we performed sex-specific expression quantitative trait locus (eQTL) analysis and sex-specific age-related differential expression analysis for genes mapped to Parkinson's disease risk loci. Through conditional/conjunctional FDR analysis we found 11 loci shared between Parkinson's disease and the sex-specific traits age at menarche and age at menopause. Gene-set and pathway analysis of the genes mapped to these loci highlighted the importance of the immune response in determining an increased disease incidence in the male population. Moreover, we highlighted a total of nine genes whose expression or age-related expression in the human brain is influenced by genetic variants in a sex-specific manner. With these analyses we demonstrated that the lack of clear sex-specific differences in allele frequencies for Parkinson's disease loci does not exclude a genetic contribution to differences in disease incidence. Moreover, further studies are needed to elucidate the role that the candidate genes identified here could have in determining a higher incidence of Parkinson's disease in the male population.
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Enfermedad de Parkinson , Humanos , Femenino , Masculino , Enfermedad de Parkinson/genética , Estudio de Asociación del Genoma Completo , Caracteres Sexuales , Fenotipo , EncéfaloRESUMEN
The relative contributions of genetic variation and experience in shaping the morphology of the adolescent brain are not fully understood. Using longitudinal data from 11,665 subjects in the ABCD Study, we fit vertex-wise variance components including family effects, genetic effects, and subject-level effects using a computationally efficient framework. Variance in cortical thickness and surface area is largely attributable to genetic influence, whereas sulcal depth is primarily explained by subject-level effects. Our results identify areas with heterogeneous distributions of heritability estimates that have not been seen in previous work using data from cortical regions. We discuss the biological importance of subject-specific variance and its implications for environmental influences on cortical development and maturation.
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Corteza Cerebral , Imagen por Resonancia Magnética , Humanos , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/anatomía & histología , Corteza Cerebral/diagnóstico por imagen , Masculino , Femenino , Adolescente , Estudios Longitudinales , Interacción Gen-Ambiente , Niño , AmbienteRESUMEN
Epidemiological and clinical studies have found associations between depression and cardiovascular disease risk factors, and coronary artery disease patients with depression have worse prognosis. The genetic relationship between depression and these cardiovascular phenotypes is not known. We here investigated overlap at the genome-wide level and in individual loci between depression, coronary artery disease and cardiovascular risk factors. We used the bivariate causal mixture model (MiXeR) to quantify genome-wide polygenic overlap and the conditional/conjunctional false discovery rate (pleioFDR) method to identify shared loci, based on genome-wide association study summary statistics on depression (n = 450,619), coronary artery disease (n = 502,713) and nine cardiovascular risk factors (n = 204,402-776,078). Genetic loci were functionally annotated using FUnctional Mapping and Annotation (FUMA). Of 13.9K variants influencing depression, 9.5K (SD 1.0K) were shared with body-mass index. Of 4.4K variants influencing systolic blood pressure, 2K were shared with depression. ConjFDR identified 79 unique loci associated with depression and coronary artery disease or cardiovascular risk factors. Six genomic loci were associated jointly with depression and coronary artery disease, 69 with blood pressure, 49 with lipids, 9 with type 2 diabetes and 8 with c-reactive protein at conjFDR < 0.05. Loci associated with increased risk for depression were also associated with increased risk of coronary artery disease and higher total cholesterol, low-density lipoprotein and c-reactive protein levels, while there was a mixed pattern of effect direction for the other risk factors. Functional analyses of the shared loci implicated metabolism of alpha-linolenic acid pathway for type 2 diabetes. Our results showed polygenic overlap between depression, coronary artery disease and several cardiovascular risk factors and suggest molecular mechanisms underlying the association between depression and increased cardiovascular disease risk.
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Proteína C-Reactiva/genética , Enfermedades Cardiovasculares/genética , Enfermedad de la Arteria Coronaria/genética , Depresión/genética , Diabetes Mellitus Tipo 2/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND AND AIMS: Increasing evidence suggests that some reproductive factors/hazards are associated with a future risk of cardiovascular disease (CVD) in women. While major (non-perinatal) depression has consistently been associated with CVD, the long-term risk of CVD after perinatal depression (PND) is largely unknown. METHODS: A nationwide population-based matched cohort study involving 55 539 women diagnosed with PND during 2001-14 in Sweden and 545 567 unaffected women individually matched on age and year of conception/delivery was conducted. All women were followed up to 2020. Perinatal depression and CVD were identified from Swedish national health registers. Using multivariable Cox models, hazard ratios (HR) of any and type-specific CVD according to PND were estimated. RESULTS: The mean age at the PND diagnosis was 30.8 [standard deviation (SD) 5.6] years. During the follow-up of up to 20 years (mean 10.4, SD 3.6), 3533 (6.4%) women with PND (expected number 2077) and 20 202 (3.7%) unaffected women developed CVD. Compared with matched unaffected women, women with PND had a 36% higher risk of developing CVD [adjusted HR = 1.36, 95% confidence interval (CI): 1.31-1.42], while compared with their sisters, women with PND had a 20% higher risk of CVD (adjusted HR = 1.20, 95% CI 1.07-1.34). The results were most pronounced in women without a history of psychiatric disorder (P for interaction < .001). The association was observed for all CVD subtypes, with the highest HR in the case of hypertensive disease (HR = 1.50, 95% CI: 1.41-1.60), ischaemic heart disease (HR = 1.37, 95% CI: 1.13-1.65), and heart failure (HR 1.36, 95% CI: 1.06-1.74). CONCLUSIONS: Women with PND are at higher risk of CVD in middle adulthood. Reproductive history, including PND, should be considered in CVD risk assessments of women.
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Enfermedades Cardiovasculares , Humanos , Femenino , Suecia/epidemiología , Adulto , Enfermedades Cardiovasculares/epidemiología , Embarazo , Factores de Riesgo , Complicaciones del Embarazo/epidemiología , Depresión/epidemiologíaRESUMEN
The linear mixed-effects model (LME) is a versatile approach to account for dependence among observations. Many large-scale neuroimaging datasets with complex designs have increased the need for LME; however LME has seldom been used in whole-brain imaging analyses due to its heavy computational requirements. In this paper, we introduce a fast and efficient mixed-effects algorithm (FEMA) that makes whole-brain vertex-wise, voxel-wise, and connectome-wide LME analyses in large samples possible. We validate FEMA with extensive simulations, showing that the estimates of the fixed effects are equivalent to standard maximum likelihood estimates but obtained with orders of magnitude improvement in computational speed. We demonstrate the applicability of FEMA by studying the cross-sectional and longitudinal effects of age on region-of-interest level and vertex-wise cortical thickness, as well as connectome-wide functional connectivity values derived from resting state functional MRI, using longitudinal imaging data from the Adolescent Brain Cognitive DevelopmentSM Study release 4.0. Our analyses reveal distinct spatial patterns for the annualized changes in vertex-wise cortical thickness and connectome-wide connectivity values in early adolescence, highlighting a critical time of brain maturation. The simulations and application to real data show that FEMA enables advanced investigation of the relationships between large numbers of neuroimaging metrics and variables of interest while considering complex study designs, including repeated measures and family structures, in a fast and efficient manner. The source code for FEMA is available via: https://github.com/cmig-research-group/cmig_tools/.
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Conectoma , Imagen por Resonancia Magnética , Adolescente , Humanos , Imagen por Resonancia Magnética/métodos , Estudios Transversales , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Conectoma/métodos , AlgoritmosRESUMEN
Ageing is a heterogeneous multisystem process involving different rates of decline in physiological integrity across biological systems. The current study dissects the unique and common variance across body and brain health indicators and parses inter-individual heterogeneity in the multisystem ageing process. Using machine-learning regression models on the UK Biobank data set (N = 32,593, age range 44.6-82.3, mean age 64.1 years), we first estimated tissue-specific brain age for white and gray matter based on diffusion and T1-weighted magnetic resonance imaging (MRI) data, respectively. Next, bodily health traits, including cardiometabolic, anthropometric, and body composition measures of adipose and muscle tissue from bioimpedance and body MRI, were combined to predict 'body age'. The results showed that the body age model demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. The correlation between body age and brain age predictions was 0.62 for the T1 and 0.64 for the diffusion-based model, indicating a degree of unique variance in brain and bodily ageing processes. Bayesian multilevel modelling carried out to quantify the associations between health traits and predicted age discrepancies showed that higher systolic blood pressure and higher muscle-fat infiltration were related to older-appearing body age compared to brain age. Conversely, higher hand-grip strength and muscle volume were related to a younger-appearing body age. Our findings corroborate the common notion of a close connection between somatic and brain health. However, they also suggest that health traits may differentially influence age predictions beyond what is captured by the brain imaging data, potentially contributing to heterogeneous ageing rates across biological systems and individuals.
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Envejecimiento , Aprendizaje Automático , Imagen por Resonancia Magnética , Humanos , Persona de Mediana Edad , Anciano , Adulto , Masculino , Envejecimiento/fisiología , Femenino , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Composición Corporal/fisiología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/anatomía & histología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/anatomía & histología , Teorema de BayesRESUMEN
BACKGROUND: Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not been fully known. This study aims to systematically investigate the phenotypic and genetic correlation between RA and CVD. METHODS: Based on UK Biobank, we conducted two cohort studies to evaluate the phenotypic relationships between RA and CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke. Next, we used linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and bivariate causal mixture model (MiXeR) methods to examine the genetic correlation and polygenic overlap between RA and CVD, using genome-wide association summary statistics. Furthermore, we explored specific shared genetic loci by conjunctional false discovery rate analysis and association analysis based on subsets. RESULTS: Compared with the general population, RA patients showed a higher incidence of CVD (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.15-1.28). We observed positive genetic correlations of RA with AF and stroke, and a mixture of negative and positive local genetic correlations underlying the global genetic correlation for CAD and HF, with 13 ~ 33% of shared genetic variants for these trait pairs. We further identified 23 pleiotropic loci associated with RA and at least one CVD, including one novel locus (rs7098414, TSPAN14, 10q23.1). Genes mapped to these shared loci were enriched in immune and inflammatory-related pathways, and modifiable risk factors, such as high diastolic blood pressure. CONCLUSIONS: This study revealed the shared genetic architecture of RA and CVD, which may facilitate drug target identification and improved clinical management.
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Artritis Reumatoide , Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Insuficiencia Cardíaca , Accidente Cerebrovascular , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudio de Asociación del Genoma Completo/métodos , Predisposición Genética a la Enfermedad/genética , Artritis Reumatoide/genética , Artritis Reumatoide/epidemiología , Enfermedad de la Arteria Coronaria/genética , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Childhood maltreatment (CM) has been indicated in adverse health outcomes across the lifespan, including severe infection-related outcomes. Yet, data are scarce on the potential role of CM in severe COVID-19-related outcomes as well as on mechanisms underlying this association. METHODS: We included 151,427 individuals in the UK Biobank who responded to questions on the history of CM in 2016 and 2017 and were alive on January 31, 2020. Binomial logistic regression models were performed to estimate the association between a history of CM and severe COVID-19 outcomes (i.e. hospitalization or death due to COVID-19), as well as COVID-19 diagnosis and vaccination as secondary outcomes. We then explored the potential mediating roles of socio-economic status, lifestyle and pre-pandemic comorbidities, and the effect modification by polygenic risk score for severe COVID-19 outcomes. RESULTS: The mean age of the study population at the start of the pandemic was 67.7 (SD = 7.72) years, and 56.5% were female. We found the number of CM types was associated with the risk of severe COVID-19 outcomes in a graded manner (pfor trend < 0.01). Compared to individuals with no history of CM, individuals exposed to any CM were more likely to be hospitalized or die due to COVID-19 (odds ratio [OR] = 1.54 [95%CI 1.31-1.81]), particularly after physical neglect (2.04 [1.57-2.62]). Largely comparable risk patterns were observed across groups of high vs. low genetic risks for severe COVID-19 outcomes (pfor difference > 0.05). Mediation analysis revealed that 50.9% of the association between CM and severe COVID-19 outcomes was explained by suboptimal socio-economic status, lifestyle, and pre-pandemic diagnosis of psychiatric disorders or other chronic medical conditions. In contrast, any CM exposure was only weakly associated with COVID-19 diagnosis (1.06 [1.01-1.12]) while significantly associated with not being vaccinated for COVID-19 (1.21 [1.13-1.29]). CONCLUSIONS: Our results add to the growing knowledge base indicating the role of childhood maltreatment in negative health outcomes across the lifespan, including severe COVID-19-related outcomes. The identified factors underlying this association represent potential intervention targets for mitigating the harmful effects of childhood maltreatment in COVID-19 and similar future pandemics.
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COVID-19 , Hospitalización , Humanos , COVID-19/epidemiología , COVID-19/mortalidad , Femenino , Hospitalización/estadística & datos numéricos , Masculino , Anciano , Persona de Mediana Edad , Estudios de Cohortes , Reino Unido/epidemiología , Maltrato a los Niños , Factores de Riesgo , SARS-CoV-2 , NiñoRESUMEN
BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969⬠women (and up to 55,568⬠male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.
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Enfermedad Coronaria , Hipertensión Inducida en el Embarazo , Nacimiento Prematuro , Embarazo , Niño , Femenino , Recién Nacido , Masculino , Humanos , Mortinato/epidemiología , Mortinato/genética , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/genética , Estudios de Cohortes , Hipertensión Inducida en el Embarazo/epidemiología , Hipertensión Inducida en el Embarazo/genética , Resultado del Embarazo/epidemiología , Retardo del Crecimiento Fetal , Padres , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genéticaRESUMEN
BACKGROUND: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. METHODS: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. RESULTS: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (ß = - 0.11, 95% CI [- 0.12, - 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (ß = - 0.07, 95% CI [- 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. CONCLUSIONS: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.
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Menarquia , Salud Mental , Niño , Femenino , Adolescente , Humanos , Estudios de Cohortes , Causalidad , Análisis de la Aleatorización MendelianaRESUMEN
STUDY QUESTION: Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? SUMMARY ANSWER: Genetic instruments suggest that higher fasting insulin may increase infertility in women. WHAT IS KNOWN ALREADY: Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. STUDY DESIGN, SIZE, DURATION: This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 68â882 women (average age 30, involved in 81â682 pregnancies) and 47â474 of their male partners (average age 33, 55â744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). MAIN RESULTS AND THE ROLE OF CHANCE: In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. LIMITATIONS, REASONS FOR CAUTION: We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. WIDER IMPLICATIONS OF THE FINDINGS: Treatments for lower fasting insulin levels may reduce the risk of infertility in women. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.