Fine-mapping inflammatory bowel disease loci to single-variant resolution.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Defining the genetic control of human blood plasma N-glycome using genome-wide association study.

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.

Fostering Healthy Futures Preventive Intervention for Children in Foster Care: Long-term Delinquency Outcomes from a Randomized Controlled Trial.

Child maltreatment and foster care placement are strong risk factors for delinquency and juvenile justice involvement, and there is substantial crossover between youth in the child welfare and juvenile justice systems. This study examines the long-term impact of the Fostering Healthy Futures (FHF) program, a 30-week mentoring and skills group preventive intervention for preadolescent maltreated children in foster care. Participants included 426 children recently placed in out-of-home care who were randomized to intervention or control conditions. Outcomes included both self-reported delinquency, measured at multiple time points between 6 months and 12 years post-intervention, as well as court records of delinquency charges, which were measured for 7 consecutive years beginning 3 months after the intervention began. Results from multilevel models indicated that the intervention group self-reported 30-82% less total and non-violent delinquency than the control group between ages 14 and 18. Court charges for total and violent delinquency in mid-adolescence were also 15-30% lower for the intervention group. These findings indicate that a mentoring and skills training program in preadolescence can reduce delinquency and justice involvement for children who are at high risk for these outcomes.

Prospective associations, longitudinal patterns of childhood socioeconomic status, and white matter organization in adulthood.

The association between childhood socioeconomic status (SES) and brain development is an emerging area of research. The primary focus to date has been on SES and variations in gray matter structure with much less known about the relation between childhood SES and white matter structure. Using a longitudinal study of SES, with measures of income-to-needs ratio (INR) at age 9, 13, 17, and 24, we examined the prospective relationship between childhood SES (age 9 INR) and white matter organization in adulthood using diffusion tensor imaging. We also examined how changes in INR from childhood through young adulthood are associated with white matter organization in adult using a latent growth mixture model. Using tract-based spatial statistics (TBSS) we found that there is a significant prospective positive association between childhood INR and white matter organization in the bilateral uncinate fasciculus, bilateral cingulum bundle, bilateral superior longitudinal fasciculus, and corpus callosum (p < .05, FWE corrected). The probability that an individual was in the high-increasing INR profile across development compared with the low-increasing INR profile was positively associated with white matter organization in the bilateral uncinate fasciculus, left cingulum, and bilateral superior longitudinal fasciculus. The results of the current study have potential implications for interventions given that early childhood poverty may have long-lasting associations with white matter structure. Furthermore, trajectories of socioeconomic status during childhood are important-with individuals that belong to the latent profile that had high increases in INR having greater regional white matter organization in adulthood.

Parental buffering in the context of poverty: positive parenting behaviors differentiate young children's stress reactivity profiles.

Experiencing poverty increases vulnerability for dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning and compromises long-term health. Positive parenting buffers children from HPA axis reactivity, yet this has primarily been documented among families not experiencing poverty. We tested the theorized power of positive parenting in 124 parent-child dyads recruited from Early Head Start (Mage = 25.21 months) by examining child cortisol trajectories using five samples collected across a standardized stress paradigm. Piecewise latent growth models revealed that positive parenting buffered children's stress responses when controlling for time of day, last stress task completed, and demographics. Positive parenting also interacted with income such that positive parenting was especially protective for cortisol reactivity in families experiencing greater poverty. Findings suggest that positive parenting behaviors are important for protecting children in families experiencing low income from heightened or prolonged physiologic stress reactivity to an acute stressor.

Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.

Intensity, not emotion: The role of poverty in emotion labeling ability in middle childhood.

Poverty exposure has been linked to difficulties in emotion expression recognition, which further increases risks for negative emotional outcomes among children. The current study aimed to investigate whether the difficulties in emotion expression recognition among children experiencing poverty may be emotion specific or expression intensity specific. Thus, the current study investigated the relationship between poverty exposure and emotion labeling ability in an ethnically and economically diverse sample of children (N = 46) in middle childhood. A novel experimental design measured emotion labeling ability at different valences of emotion (fearful, angry, and happy) and at varying intensities (0-100%) of emotion presentation. Using a hierarchical logistic regression, we found a significant interaction between the percentage of time since birth a child has lived in poverty and the intensity of the emotional stimulus in affecting correct emotion identification. Children who lived longer in poverty gained less accuracy for equivalent increases in intensity compared with children who had not lived in poverty. On average, children who chronically lived in poverty required emotional intensity set at 60% in order to reach levels of accuracy observed at 30% intensity among children who were never exposed to poverty. We found no significant emotion-specific effect. These findings demonstrate that children who experience chronic poverty require more intense expressions to recognize emotions across valences. This further elaborates the existing understanding of a relationship between poverty exposure and emotion recognition, informing future studies examining expression recognition as a mechanism involved in developing psychopathology.

Cross-Country Differences in Parental Reporting of Symptoms of ADHD.

Previous studies within the United States suggest there are cultural and contextual influences on how Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms are perceived. If such influences operate within a single country, they are likely to also occur between countries. In the current study, we tested whether country differences in mean ADHD scores also reflect cultural and contextual differences, as opposed to actual etiological differences. The sample for the present study included 974 participants from four countries tested at two-time points, the end of preschool and the end of 2nd grade. Consistent with previous research, we found lower mean ADHD scores in Norway and Sweden in comparison to Australia and the United States, and we tested four explanations for these country differences: 1) Genuine etiological differences, 2) Slower introduction to formal academic skills in Norway and Sweden than in the United States and Australia that indicated a context difference, 3) Under-reporting tendency in Norway and Sweden, or 4) Over-reporting tendency in the United States and Australia. Either under-or over-reporting would be examples of cultural differences in the perception of ADHD symptoms. Of these explanations, results of ADHD measurement equivalence tests across countries rejected the first three explanations and supported the fourth explanation: an over-reporting tendency in the United States and Australia. These findings indicate that parental reporting of ADHD symptoms is more accurate in Norway and Sweden than in Australia and the United States, and thus have important clinical and educational implications for how parental reporting informs an ADHD diagnosis in these countries.

The effects of economic and sociocultural stressors on the well-being of children of Latino immigrants living in poverty.

OBJECTIVE: This article explored whether preschoolers' physical (body mass index [BMI] and salivary cortisol levels) and psychological (internalizing/externalizing behaviors) well-being were predicted by economic hardship, as has been previously documented, and further, whether parental immigration-related stress and/or acculturation level moderated this relationship in low-income Latino families. METHOD: The sample for the current study included 71 children of Latino immigrants (M = 4.46 years, SD = .62). Parents completed questionnaires assessing immigration-related stress, acculturation level, economic hardship, and child internalizing and externalizing behaviors. Child's BMI was also calculated from height and weight. Salivary cortisol samples were collected midmorning and midafternoon at home on non-child-care days. Salivary cortisol values were averaged and log transformed. RESULTS: Children's salivary cortisol was predicted by an interaction between economic hardship and acculturation, with lower cortisol values except when children were protected by both lower acculturation and lower economic hardship. Both internalizing and externalizing behaviors were predicted by an interaction between economic hardship and immigration-related stress, with highest behaviors among children whose parents reported high levels of both economic hardship and immigration-related stress. CONCLUSIONS: The effects of economic hardship on the well-being of young children of Latino immigrants may depend on concurrent experiences of sociocultural stress, with detrimental effects emerging for these outcomes only when economic hardship and sociocultural stressors are high. (PsycINFO Database Record

The Impact of Program Structure on Cortisol Patterning in Children Attending Out-of-Home Child Care.

Full-day center-based child care has repeatedly been associated with rising levels of cortisol, a hormone that helps the body manage challenge, across the day at child care. This article presents findings from two studies examining the relationship between child care program structure (number of days per week, and hours per day) and cortisol production across the day. Study 1 presents findings comparing cortisol production in 3- to 5-year-old children enrolled in either full-day (N = 55) or half-day (N = 63) Head-Start-funded programs. Study 2 presents findings comparing young children enrolled in either full-day full-time (5 days per week; N = 37) or full-day part-time (2-3days/week; N = 41) primarily tuition-funded programs. Using multilevel modeling and controlling for a number of child factors, attending full-day, full-time programs (as compared to either half-day or part-time programs) was associated with increased cortisol production across the day on child care and home days. Implications for early childhood educators are discussed.

Self-Regulation and Economic Stress in Children of Hispanic Immigrants and Their Peers: Better Regulation at a Cost?

RESEARCH FINDINGS: Although there is a well-established relationship between economic stress and children's self-regulation, few studies have examined this relationship in children of Hispanic immigrants (COHIs), a rapidly growing population. In a sample of preschool children (N = 165), we examined whether economic stress predicted teacher evaluations of children's self-regulation, whether economic stress predicted children's physiological reactivity (via cortisol levels), and whether economic stress had a similar effect on self-regulation and children's cortisol for COHI versus nonimmigrant children. Greater economic stress was associated with poorer child self-regulation and heightened physiological reactivity across a challenging classroom task for the sample as a whole. However, when we examined children by group, greater economic stress was associated with poorer teacher-reported self-regulation for nonimmigrant children only. In contrast, greater economic stress was related to greater cortisol reactivity across a challenge task for COHIs but not for nonimmigrants. PRACTICE OR POLICY: Results demonstrate the importance of considering physiological indices of self-regulation (heightened stress physiology), in addition to traditional external indices (teacher report), when assessing self-regulation or risk more generally among preschool samples that are diverse in terms of ethnicity, economic risk, and parents' nativity.

Prenatal Programming of Postnatal Susceptibility to Memory Impairments: A Developmental Double Jeopardy.

In the study reported here, we examined the effects of fetal exposure to a synthetic stress hormone (synthetic glucocorticoids) on children's susceptibility to postnatal sociodemographic adversity. We recruited children who were born healthy and at term. Twenty-six had been treated with steroid hormones (glucocorticoids) during the prenatal period, and 85 had not. Only children exposed to both prenatal stress hormones and postnatal sociodemographic adversity showed impaired performance on standardized tests of memory function. The association was specific to long-term memory. General intellectual functioning and expressive language were not affected by fetal glucocorticoid exposure. Results were independent of maternal intelligence and maternal depression at the time of the study. These findings are consistent with a vulnerability-stress model: Prenatal exposure to synthetic stress hormones is associated with increased susceptibility to subsequent adversity, with consequences for cognitive functioning that persist 6 to 10 years after birth.

The role of paternal and maternal warmth and hostility on daughter's psychosocial outcomes: The insidious effects of father warmth combined with high paternal hostility.

Introduction: Despite the well-accepted view on the importance of parental warmth and parental hostility for adolescent development, few studies have examined the joint interactive effects of these two key aspects of parenting. Furthermore, research comparing maternal and paternal parenting is limited, with the father-daughter relationship during adolescence remaining one of the more understudied familial contexts. Given that family processes are key for the intergenerational transmission of inequality, these parent-child relationships may be especially important for youth at risk for exposure to violence. Objectives: Using a sample of juvenile female offenders, this study examined the associations between the perceived warmth and hostility in the father-daughter and mother-daughter relationships on daughters' depressive symptoms, anxiety symptoms, romantic partner warmth, romantic partner hostility, and the daughter's sense of agency. We hypothesized that high perceived parental warmth would moderate the effects of parental hostility by protecting daughters from the negative effects of parental hostility, with stronger effects for the father-daughter than the mother-daughter relationship. Results: In contrast, our paternal relationship findings across four of the five outcomes suggest a moderation in the opposite direction - that is, high perceived father warmth exacerbates the deleterious effects of father hostility on daughters' depressive symptoms, anxiety, romantic partner warmth, and romantic partner hostility. Maternal warmth, and not hostility, had a direct association with these four outcomes, with stronger explanatory power shown for the father-daughter than the mother-daughter model. Higher agency was associated with maternal hostility only. Conclusion: Our findings suggest that daughters might be modeling and internalizing the relationship with their fathers (for better or worse) when they perceive it as warm and supportive. Consequently, adolescent girls whose fathers exhibit hostile behavior may benefit from emotional distancing from their fathers.

Trauma appraisals and posttraumatic growth among survivors of sexual assault.

OBJECTIVE: Trauma survivors often endorse some level of posttraumatic growth (PTG), referring to positive outcomes after trauma related to meaning-making and strengthened perceptions of the self. While extant research points to cognitive processes at the root of PTG, posttrauma cognitions such as shame, fear, and self-blame have thus far only been linked to negative outcomes of trauma exposure. The current study examines the association between posttrauma appraisals and PTG among victims of interpersonal violence. Findings will reveal whether appraisals directed toward the self (shame and self-blame), toward the world (anger and fear), or those directed toward relationships (betrayal and alienation) are most conducive to growth. METHOD: A sample of 216 adult women aged 18-64 years were interviewed at baseline and 3, 6, and 9 months later as part of a larger study on social reactions received when disclosing sexual assault. As part of the interview battery, they were administered the Posttraumatic Growth Inventory (PTGI) and Trauma Appraisal Questionnaire. Posttrauma appraisals were used as time-invariant predictors of PTG (PTGI score) at each of the four time points. RESULTS: Posttrauma appraisals of betrayal were associated with initial PTG and alienation appraisals predicted increases in PTG over time. However, self-blame and shame did not predict PTG. CONCLUSIONS: Results suggest that a violation to one's views of interpersonal relationships, reflected in experiences of alienation and betrayal posttrauma, may be especially relevant for growth. As PTG reduces distress among trauma victims, this finding suggests targeting maladaptive interpersonal appraisals is an important intervention target. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Arrested development: the effects of incarceration on the development of psychosocial maturity.

Improvements in temperance, perspective, and responsibility are a part of typical development of psychosocial maturity during adolescence. The existing literature suggests that the developmental course of psychosocial maturity is influenced by normative variations in social context, but little is known about how atypical contexts, such as incarceration, influence its development. The study investigates how the development of psychosocial maturity is affected by incarceration, using data from a 7-year longitudinal study of 1,171 adolescent males. We compared the effects of confinement in juvenile facilities with varying degrees of focus on incarceration versus rehabilitation (i.e., secure vs. residential treatment facilities) and tested whether facility quality and age at incarceration moderate the effect of incarceration on psychosocial maturity. The results indicate that incarceration in a secure setting, but not a residential treatment facility, is associated with a short-term decline in temperance and responsibility. The total amount of time incarcerated in a residential treatment facility, but not a secure setting, had a negative effect on the developmental trajectory of psychosocial maturity. Age at incarceration, but not the facility quality, moderated the effect of recent incarceration: older youths were more susceptible to short-term negative effects of recent incarceration in a secure setting, but they also benefited more than younger participants from short-term positive effects of incarceration in a residential treatment setting. Furthermore, youths who perceived their incarceration setting as unsafe evinced a decline in temperance. Future research and policy implications are discussed.

Understanding Cortisol Reactivity across the Day at Child Care: The Potential Buffering Role of Secure Attachments to Caregivers.

Full-day center-based child care has been repeatedly associated with rising cortisol across the child care day. This study addressed the potential buffering role of attachment to mothers and lead teachers in 110 preschoolers while at child care. Using multi-level modeling and controlling for a number of child, family, and child care factors, children with more secure attachments to teachers were more likely to show falling cortisol across the child care day. Attachment to mothers interacted with child care quality, with buffering effects found for children with secure attachments attending higher quality child care. Implications for early childhood educators are discussed.

Are secondary variants of juvenile psychopathy more reactively violent and less psychosocially mature than primary variants?

There is growing support for the disaggregation of psychopathy into primary and secondary variants. This study examines whether variants of psychopathy can be identified in a subsample (n = 116) of juvenile offenders with high scores on the Youth Version of the Psychopathy Checklist (PCL:YV). Model-based cluster analysis of offenders' scores on the PCL:YV and a measure of anxiety suggested a two-group solution. The derived clusters manifested expected differences across theoretically relevant constructs of abuse history, hostility, and psychiatric symptoms. Compared with low-anxious primary variants, high-anxious secondary variants manifested more institutional violence, greater psychosocial immaturity, and more instability in institutional violence over a 2-year period, but similar stability in PCL:YV scores.

The development of criminal style in adolescence and young adulthood: separating the lemmings from the loners.

Despite broad consensus that most juvenile crimes are committed with peers, many questions regarding developmental and individual differences in criminal style (i.e., co-offending vs. solo offending) remain unanswered. Using prospective 3-year longitudinal data from 937 14- to 17-year-old serious male offenders, the present study investigates whether youths tend to offend alone, in groups, or a combination of the two; whether these patterns change with age; and whether youths who engage in a particular style share distinguishing characteristics. Trajectory analyses examining criminal styles over age revealed that, while most youth evinced both types of offending, two distinct groups emerged: an increasingly solo offender trajectory (83%); and a mixed style offender trajectory (17%). Alternate analyses revealed (5.5%) exclusively solo offenders (i.e., only committed solo offenses over 3 years). There were no significant differences between groups in individuals' reported number of friends, quality of friendships, or extraversion. However, the increasingly solo and exclusively solo offenders reported more psychosocial maturity, lower rates of anxiety, fewer psychopathic traits, less gang involvement and less self reported offending than mixed style offenders. Findings suggest that increasingly and exclusively solo offenders are not loners, as they are sometimes portrayed, and that exclusively solo offending during adolescence, while rare and previously misunderstood, may not be a risk factor in and of itself.

Dependence in adult relationships: Latent classes of relational dependence and associated outcomes in women exposed to intimate partner abuse.

OBJECTIVE: Studies applying a betrayal trauma theory (BTT) framework to adult abuse have measured dependence by asking about the closeness of the victim-offender relationship. However, women's experiences of dependence may vary even in close victim-offender relationships, such as in the case of abuse perpetrated by intimate partners. This investigation assessed whether subgroups of women who were abused by intimate partners could be identified based on dependence characteristics. Further, we evaluated whether high-dependence subgroups were more likely to experience outcomes associated with BTT. METHOD: Using latent class analysis (LCA), we examined classes of dependence in a non-treatment-seeking community sample of 236 women who reported intimate partner abuse (IPA) to police. The validity of the dependence classes was evaluated from a BTT perspective using the classes to predict empirically supported betrayal-trauma outcomes. RESULTS: Low-, medium-, and high-dependence subgroups emerged when dependence characteristics were analyzed using LCA. As hypothesized, greater dependence was linked with increased likelihood of women maintaining the relationship with the offender, higher self-report dissociation scores, and greater service disengagement. Counter to study hypotheses, dependence subgroups were unrelated to women's revictimization and self-reported memory for the target IPA incident 12 months later. CONCLUSION: Findings suggest that dependence can vary even in close adult relationships. Further, we identified links between dependence subgroups and outcomes predicted by BTT. Implications for BTT research and IPA victim support and intervention are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Women's Experiences of Social Reactions From Informal and Formal Supports: Using a Modified Administration of the Social Reactions Questionnaire.

A growing literature links social reactions to disclosures of intimate violence to posttraumatic outcomes. The Social Reactions Questionnaire (SRQ), a widely used measure developed to assess social reactions, asks about reactions received from people generally. The ability to examine the impact of social reactions from specific groups of people-such as criminal justice personnel versus community-based providers-has become increasingly more important from both research and practice perspectives. For example, as sexual assault responses nationally have relied on community-coordinated models that involve both criminal justice and community-based systems, tools are lacking to systematically assess the impact of social reactions from criminal justice personnel and community-based providers on survivors. Using the SRQ, the current study asked women to report separately on reactions received from criminal justice personnel, community-based providers, and informal supports. We recruited a diverse community sample of women (N = 228, ages 18-63, 19% lesbian/bisexual, 44% ethnic minority) who experienced a sexual assault in the previous year and disclosed to the criminal justice system and/or a community-based provider. Multilevel analyses revealed considerable variability in the social reactions reported by women across criminal justice personnel, community-based providers, and informal supports. Analyses supported a seven-factor structure for the SRQ when the measure is yoked to particular experiences of disclosure, in this case to criminal justice personnel, community-based providers, or informal supports. The utility of this modified administration and scoring of the SRQ and the importance of considering reactions across different groups are described.