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Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1-3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain-behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available-with a total sample size of around 50,000 individuals-to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain-phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.
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Mapeo Encefálico , Encéfalo , Imagen por Resonancia Magnética , Mapeo Encefálico/métodos , Cognición , Conjuntos de Datos como Asunto , Humanos , Imagen por Resonancia Magnética/métodos , Neuroimagen , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.
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Melanoma , Neoplasias Cutáneas , Humanos , Alelos , Melanoma/genética , Melanoma/metabolismo , Linfocitos T CD8-positivos/metabolismo , Neoplasias Cutáneas/genética , Histocompatibilidad , Antígenos de Histocompatibilidad Clase I/genéticaRESUMEN
For more than half a century, Denmark has maintained population-wide demographic, health care, and socioeconomic registers that provide detailed information on the interaction between all residents and the extensive national social services system. We leverage this resource to reconstruct the genealogy of the entire nation based on all individuals legally residing in Denmark since 1968. We cross-reference 6,691,426 individuals with nationwide health care registers to estimate heritability and genetic correlations of 10 broad diagnostic categories involving all major organs and systems. Heritability estimates for mental disorders were consistently the highest across demographic cohorts (average h2 = 0.406, 95% CI = [0.403, 0.408]), whereas estimates for cancers were the lowest (average h2 = 0.130, 95% CI = [0.125, 0.134]). The average genetic correlation of each of the 10 diagnostic categories with the other nine was highest for gastrointestinal conditions (average rg = 0.567, 95% CI = [0.566, 0.567]) and lowest for urogenital conditions (average rg = 0.386, 95% CI = [0.385, 0.388]). Mental, pulmonary, gastrointestinal, and neurological conditions had similar genetic correlation profiles.
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Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad/genética , Dinamarca , Investigación sobre Servicios de Salud/métodos , Humanos , Trastornos Mentales/diagnóstico , Trastornos Mentales/genéticaRESUMEN
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
BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.
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BACKGROUND: To investigate relationships among different physical health problems in a large, sociodemographically diverse sample of 9-to-10-year-old children and determine the extent to which perinatal health factors are associated with childhood physical health problems. METHODS: A cross-sectional study was conducted utilizing the Adolescent Brain Cognitive Developmentâ (ABCD) Study (n = 7613, ages 9-to-10-years-old) to determine the associations among multiple physical health factors (e.g., prenatal complications, current physical health problems). Logistic regression models controlling for age, sex, pubertal development, household income, caregiver education, race, and ethnicity evaluated relationships between perinatal factors and childhood physical health problems. RESULTS: There were significant associations between perinatal and current physical health measures. Specifically, those who had experienced perinatal complications were more likely to have medical problems by 9-to-10 years old. Importantly, sleep disturbance co-occurred with several physical health problems across domains and developmental periods. CONCLUSION: Several perinatal health factors were associated with childhood health outcomes, highlighting the importance of understanding and potentially improving physical health in youth. Understanding the clustering of physical health problems in youth is essential to better identify which physical health problems may share underlying mechanisms. IMPACT: Using a multivariable approach, we investigated the associations between various perinatal and current health problems amongst youth. Our study highlights current health problems, such as sleep problems at 9-to-10 years old, that are associated with a cluster of factors occurring across development (e.g., low birth weight, prenatal substance exposure, pregnancy complications, current weight status, lifetime head injury). Perinatal health problems are at large, non-modifiable (in this retrospective context), however, by identifying which are associated with current health problems, we can identify potential targets for intervention and prevention efforts.
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Characterizing the optimal fMRI paradigms for detecting behaviorally relevant functional connectivity (FC) patterns is a critical step to furthering our knowledge of the neural basis of behavior. Previous studies suggested that FC patterns derived from task fMRI paradigms, which we refer to as task-based FC, are better correlated with individual differences in behavior than resting-state FC, but the consistency and generalizability of this advantage across task conditions was not fully explored. Using data from resting-state fMRI and three fMRI tasks from the Adolescent Brain Cognitive Development Study ® (ABCD), we tested whether the observed improvement in behavioral prediction power of task-based FC can be attributed to changes in brain activity induced by the task design. We decomposed the task fMRI time course of each task into the task model fit (the fitted time course of the task condition regressors from the single-subject general linear model) and the task model residuals, calculated their respective FC, and compared the behavioral prediction performance of these FC estimates to resting-state FC and the original task-based FC. The FC of the task model fit was better than the FC of the task model residual and resting-state FC at predicting a measure of general cognitive ability or two measures of performance on the fMRI tasks. The superior behavioral prediction performance of the FC of the task model fit was content-specific insofar as it was only observed for fMRI tasks that probed similar cognitive constructs to the predicted behavior of interest. To our surprise, the task model parameters, the beta estimates of the task condition regressors, were equally if not more predictive of behavioral differences than all FC measures. These results showed that the observed improvement of behavioral prediction afforded by task-based FC was largely driven by the FC patterns associated with the task design. Together with previous studies, our findings highlighted the importance of task design in eliciting behaviorally meaningful brain activation and FC patterns.
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Encéfalo , Imagen por Resonancia Magnética , Adolescente , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Imagen por Resonancia Magnética/métodos , Modelos Lineales , IndividualidadRESUMEN
Autoimmune and autoinflammatory diseases (AIIDs) involve a deficit in an individual's immune system function, whereby the immune reaction is directed against self-antigens. Many AIIDs have a strong genetic component, but they can also be triggered by environmental factors. AIIDs often have a highly negative impact on the individual's physical and mental wellbeing. Understanding the genetic underpinning of AIIDs is thus crucial both for diagnosis and for identifying individuals at high risk of an AIID and mental illness as a result thereof. The aim of the present study was to perform systematic statistical and genetic analyses to assess the role of human leukocyte antigen (HLA) alleles in 30 AIIDs and to study the links between AIIDs and psychiatric disorders. We leveraged the Danish iPSYCH Consortium sample comprising 65 534 individuals diagnosed with psychiatric disorders or selected as part of a random population sample, for whom we also had genetic data and diagnoses of AIIDs. We employed regression analysis to examine comorbidities between AIIDs and psychiatric disorders and associations between AIIDs and HLA alleles across seven HLA genes. Our comorbidity analyses showed that overall AIID and five specific AIIDs were associated with having a psychiatric diagnosis. Our genetic analyses found 81 significant associations between HLA alleles and AIIDs. Lastly, we show connections across AIIDs, psychiatric disorders and infection susceptibility through network analysis of significant HLA associations in these disease classes. Combined, our results include both novel associations as well as replications of previously reported associations in a large sample, and highlight the genetic and epidemiological links between AIIDs and psychiatric disorders.
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Enfermedades Autoinmunes , Enfermedades Autoinflamatorias Hereditarias , Trastornos Mentales , Humanos , Predisposición Genética a la Enfermedad , Inmunogenética , Alelos , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genéticaRESUMEN
Adolescence is characterized by significant brain development and marks a period of the life span with an increased incidence of mood disorders, especially in females. The risk of developing mood disorders is also higher in individuals scoring high on neuroticism, a personality trait characterized by a tendency to experience negative and anxious emotions. We previously found in a cross-sectional study that neuroticism is associated with microstructural left-right asymmetry of the fronto-limbic white matter involved in emotional processing, with opposite effects in female and male adolescents. We now have extended this work collecting longitudinal data in 76 typically developing children and adolescents aged 7-18 years, including repeated MRI sampling up to 11 times. This enabled us, for the first time, to address the critical question, whether the association between neuroticism and frontal-limbic white matter asymmetry changes or remains stable across late childhood and adolescence. Neuroticism was assessed up to four times and showed good intraindividual stability and did not significantly change with age. Conforming our cross-sectional results, females scoring high on neuroticism displayed increased left-right cingulum fractional anisotropy (FA), while males showed decreased left-right cingulum FA asymmetry. Despite ongoing age-related increases in FA in cingulum, the association between neuroticism and cingulum FA asymmetry was already expressed in females in late childhood and remained stable across adolescence. In males, the association appeared to become more prominent during adolescence. Future longitudinal studies need to cover an earlier age span to elucidate the time point at which the relationship between neuroticism and cingulum FA asymmetry arises.
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Sustancia Blanca , Humanos , Masculino , Niño , Adolescente , Femenino , Sustancia Blanca/diagnóstico por imagen , Estudios Transversales , Neuroticismo , Estudios Longitudinales , Emociones , AnisotropíaRESUMEN
Findings in adults have shown that crystallized measures of intelligence, which are more culturally sensitive than fluid intelligence measures, have greater heritability; however, these results have not been found in children. The present study used data from 8,518 participants between 9 and 11 years old from the Adolescent Brain Cognitive Development (ABCD) Study. We found that polygenic predictors of intelligence test performance (based on genome-wide association meta-analyses of data from 269,867 individuals) and of educational attainment (based on data from 1.1 million individuals) predicted neurocognitive performance. We found that crystallized measures were more strongly associated with both polygenic predictors than were fluid measures. This mirrored heritability differences reported previously in adults and suggests similar associations in children. This may be consistent with a prominent role of gene-environment correlation in cognitive development measured by crystallized intelligence tests. Environmental and experiential mediators may represent malleable targets for improving cognitive outcomes.
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Estudio de Asociación del Genoma Completo , Inteligencia , Adulto , Niño , Humanos , Adolescente , Herencia Multifactorial , Encéfalo , CogniciónRESUMEN
BACKGROUND: Suicide risk is complex and nuanced, and how place impacts suicide risk when considered alongside detailed individual risk factors remains uncertain. We aimed to examine suicide risk in Denmark with both individual and neighbourhood level risk factors. METHODS: We used Danish register-based data to identify individuals born in Denmark from 1972, with full parental information and psychiatric diagnosis history. We fitted a two-level survival model to estimate individual and neighbourhood determinants on suicide risk. RESULTS: We identified 1723 cases of suicide in Denmark during the follow-up period from 1982 to 2015. Suicide risk was explained mainly by individual determinants. Parental comorbidities, particularly maternal schizophrenia [incidence rate ratio (IRR): 2.29, 95% CI 1.56-3.16] and paternal death (2.29, 95% CI 1.31-3.72) partly explained suicide risk when adjusted for all other determinants. The general contextual effect of suicide risk across neighbourhoods showed a median incidence rate ratio (MRR) of 1.13 (1.01-1.28), which was further reduced with full adjustment. Suicide risk increased in neighbourhoods with a higher proportion of manual workers (IRR: 1.08; 1.03-1.14), and decreased with a higher population density (IRR: 0.89; 0.83-0.96). CONCLUSION: Suicide risk varies mainly between individuals, with parental comorbidities having the largest effect on suicide risk. Suicide risk was less impacted by neighbourhood, though, albeit to a lesser extent than individual determinants, some characteristics were associated with suicide risk. Suicide prevention policies might consider targeting interventions towards individuals more vulnerable due to particular parental comorbidities, whilst taking into account that some neighbourhood characteristics might exacerbate this risk further.
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Suicidio , Humanos , Prevención del Suicidio , Factores de Riesgo , Análisis de Supervivencia , Dinamarca/epidemiologíaRESUMEN
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly increased depression rates, particularly in emerging adults. The aim of this study was to examine longitudinal changes in depression risk before and during COVID-19 in a cohort of emerging adults in the U.S. and to determine whether prior drinking or sleep habits could predict the severity of depressive symptoms during the pandemic. METHODS: Participants were 525 emerging adults from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a five-site community sample including moderate-to-heavy drinkers. Poisson mixed-effect models evaluated changes in the Center for Epidemiological Studies Depression Scale (CES-D-10) from before to during COVID-19, also testing for sex and age interactions. Additional analyses examined whether alcohol use frequency or sleep duration measured in the last pre-COVID assessment predicted pandemic-related increase in depressive symptoms. RESULTS: The prevalence of risk for clinical depression tripled due to a substantial and sustained increase in depressive symptoms during COVID-19 relative to pre-COVID years. Effects were strongest for younger women. Frequent alcohol use and short sleep duration during the closest pre-COVID visit predicted a greater increase in COVID-19 depressive symptoms. CONCLUSIONS: The sharp increase in depression risk among emerging adults heralds a public health crisis with alarming implications for their social and emotional functioning as this generation matures. In addition to the heightened risk for younger women, the role of alcohol use and sleep behavior should be tracked through preventive care aiming to mitigate this looming mental health crisis.
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COVID-19 , Adolescente , Adulto , Humanos , Femenino , COVID-19/psicología , Depresión/epidemiología , Depresión/psicología , Pandemias/prevención & control , SARS-CoV-2 , Salud MentalRESUMEN
Twin and family studies have historically aimed to partition phenotypic variance into components corresponding to additive genetic effects (A), common environment (C), and unique environment (E). Here we present the ACE Model and several extensions in the Adolescent Brain Cognitive Developmentâ Study (ABCD Study®), employed using the new Fast Efficient Mixed Effects Analysis (FEMA) package. In the twin sub-sample (n = 924; 462 twin pairs), heritability estimates were similar to those reported by prior studies for height (twin heritability = 0.86) and cognition (twin heritability between 0.00 and 0.61), respectively. Incorporating SNP-derived genetic relatedness and using the full ABCD Study® sample (n = 9,742) led to narrower confidence intervals for all parameter estimates. By leveraging the sparse clustering method used by FEMA to handle genetic relatedness only for participants within families, we were able to take advantage of the diverse distribution of genetic relatedness within the ABCD Study® sample.
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Encéfalo , Cognición , Fenotipo , Proyectos de Investigación , Polimorfismo de Nucleótido Simple/genética , Modelos GenéticosRESUMEN
Although paternal age has been linked to certain psychiatric disorders, the nature of any causal relationship remains elusive. Here, we aimed to comprehensively assess the magnitude of a wide range of offspring's psychiatric risk conferred by paternal age, leveraging a pedigree inferred from covered-insurance relationship (accuracy >98%) in Taiwan's single-payer compulsory insurance program. We also examined whether there is an independent role of paternal age and explored the potential effect of parental age difference. A total cohort of 7,264,788 individuals born between 1980 and 2018 were included; 5,572,232 with sibling(s) were selected for sibling-comparison analyses and 1,368,942 and 1,044,420 children with information of paternal-grandparents and maternal-grandparents, respectively, were selected for multi-generation analyses. Using inpatient/outpatient claims data (1997-2018), we identified schizophrenia, autism, bipolar disorder (BPD), attention deficit-hyperactivity disorder (ADHD), major depressive disorder (MDD), eating disorder (ED), substance use disorder (SUD), mental retardation (MR), tic disorder, obsessive-compulsive disorder (OCD), anxiety, and somatoform disorder. We identified suicides using death certificates. Logistic regression analysis was used to estimate the paternal/maternal/grand-paternal age association with psychiatric risk in the offspring. The total cohort and sibling-comparison cohort resulted in similar estimates. Paternal age had a U-shaped relationship with offspring's MDD, ED, SUD, and anxiety. A very young maternal age (<20 years) was associated with markedly higher risk in offspring's SUD, MR, and suicide. Older paternal age (>25 years) was linearly associated with offspring's schizophrenia, autism, BPD, ADHD, MDD, ED, SUD, MR, OCD, anxiety, and suicide. Older grand-paternal age was linearly associated with offspring's schizophrenia, autism, ADHD, and MR. Dissimilar parental age was positively associated with offspring's ADHD, MDD, SUD, MR, anxiety, and suicide, and negatively associated with offspring's OCD. This comprehensive assessment provides solid evidence for the independent role of paternal age in psychiatric risk in the offspring and clarifies the significance of both early parenthood and delayed paternity.
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Trastorno Depresivo Mayor , Trastorno Obsesivo Compulsivo , Suicidio , Masculino , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Estudios de Cohortes , Edad Paterna , TaiwánRESUMEN
Studies suggest prenatal cannabis exposure is associated with mood/behavioral problems in children. However, it is unclear if targeting modifiable domains like sleep behaviors would improve outcomes in exposed youth. Using a causal inference framework, the effect of changing sleep-hours on changing internalizing/externalizing problems in children was examined using the Adolescent Brain Cognitive Development™ study baseline (ages 9-10; collected during 2016-2018) and year-1 follow-up data (N = 9825; 4663 female; 5196 white). Average treatment effects (ATE) indicated that more sleep predicted less internalizing (ATE = -.34, SE = .08, p < .001) and externalizing (ATE = -.29, SE = .07, p < .001) problems over time. However, prenatal cannabis exposure moderated the ATE on internalizing (conditional-ATE = .91, SE = .39, p = .019), whereby participants with exposure (n = 605) did not show any effect of changing sleep-hours on mood (B = .09, SE = .24).
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Cannabis , Problema de Conducta , Niño , Embarazo , Humanos , Adolescente , Femenino , Bosques Aleatorios , Encéfalo , Cognición , SueñoRESUMEN
The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.
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Núcleo Accumbens/citología , Obesidad Infantil/etiología , Circunferencia de la Cintura , Aumento de Peso , Recuento de Células , Niño , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Masculino , Núcleo Accumbens/diagnóstico por imagen , Obesidad Infantil/diagnóstico por imagenRESUMEN
Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.
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Citocinas/genética , Inflamación/diagnóstico , Sitios de Carácter Cuantitativo , Biomarcadores/sangre , Estudios de Cohortes , Citocinas/sangre , Citocinas/inmunología , Dinamarca , Elementos de Facilitación Genéticos/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Recién Nacido , Inflamación/sangre , Inflamación/inmunología , Masculino , Polimorfismo de Nucleótido Simple , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Subunidad beta de la Proteína de Unión al Calcio S100/inmunologíaRESUMEN
Trait stability of measures is an essential requirement for individual differences research. Functional MRI has been increasingly used in studies that rely on the assumption of trait stability, such as attempts to relate task related brain activation to individual differences in behavior and psychopathology. However, recent research using adult samples has questioned the trait stability of task-fMRI measures, as assessed by test-retest correlations. To date, little is known about trait stability of task fMRI in children. Here, we examined within-session reliability and long-term stability of individual differences in task-fMRI measures using fMRI measures of brain activation provided by the adolescent brain cognitive development (ABCD) Study Release v4.0 as an individual's average regional activity, using its tasks focused on reward processing, response inhibition, and working memory. We also evaluated the effects of factors potentially affecting reliability and stability. Reliability and stability (quantified as the ratio of non-scanner related stable variance to all variances) was poor in virtually all brain regions, with an average value of 0.088 and 0.072 for short term (within-session) reliability and long-term (between-session) stability, respectively, in regions of interest (ROIs) historically-recruited by the tasks. Only one reliability or stability value in ROIs exceeded the 'poor' cut-off of 0.4, and in fact rarely exceeded 0.2 (only 4.9%). Motion had a pronounced effect on estimated reliability/stability, with the lowest motion quartile of participants having a mean reliability/stability 2.5 times higher (albeit still 'poor') than the highest motion quartile. Poor reliability and stability of task-fMRI, particularly in children, diminishes potential utility of fMRI data due to a drastic reduction of effect sizes and, consequently, statistical power for the detection of brain-behavior associations. This essential issue urgently needs to be addressed through optimization of task design, scanning parameters, data acquisition protocols, preprocessing pipelines, and data denoising methods.