Change in Child Opportunity Index in Early Childhood Is Associated with Youth BMI Growth.

Background: The neighborhood-level child opportunity index (COI) has been used in policy-based initiatives to identify and improve low-resource neighborhoods in order to impact child health. Understanding of how changes in COI can impact child growth, however, is lacking. Methods: Participants were 1124 children from the Family Life Project, a longitudinal birth cohort of families in rural, high-poverty areas. Youth anthropometrics were measured at eight assessments (ages 2 months through 12 years). Neighborhood COI was obtained at seven assessments (ages 2 months through 5 years) and used to create seven trajectory groups representing a change in COI: stayed low on all seven assessments, stayed moderate, stayed high, left low, declined from moderate, declined from high, and bounced around. Results: As hypothesized, moving from high COI neighborhoods into lower COI neighborhoods was associated with greater BMI growth and increased risk for obesity and severe obesity at 12 years. As hypothesized, the opposite effect, which approached significance at p = 0.056, was found among children who moved from low COI neighborhoods into higher COI neighborhoods. Specifically, moving into higher COI neighborhoods was associated with reduced BMI growth, and lower risk for severe obesity at 12 years. Conclusions: Moving into higher COI neighborhoods may be associated with healthier BMI growth, while the opposite effect may occur when moving into lower COI neighborhoods. Given the use of the COI in public health initiatives and growing evidence for its potential positive impact on child growth, future work is needed to replicate our findings among larger diverse samples.

Stress-induced eating in rural adolescents: Unique variability among boys and adolescents with obesity.

Stress may contribute to the development of obesity through its effects on dysregulated eating, although this has not yet been examined among low-income, rural adolescents. We examined adolescents' stress-induced changes in eating an ad libitum meal, and after, in the absence of hunger (EAH), and the extent to which these varied by sex, race, and weight status. Participants included 260 adolescents, drawn from a sample of rural households experiencing poverty. Adolescents completed two home visits while salivary cortisol was measured; during the control (low stress) visit, they completed questionnaires and procedures thought to elicit low levels of stress and had BMI assessed. During the stress visit, adolescents completed a 20-min set of psychosocial stress challenges before eating. At each visit, adolescents consumed an ad-libitum meal after which they were additionally given large portions of snacks (EAH task). Results revealed that indeed cortisol was higher during the stress visit, across the sample. Boys showed stress-induced increases during ad-libitum meal intake (for calories, fat, and carbohydrates) whereas girls exhibited decreased intake. Further, adolescents with obesity showed stress-induced increases in fat intake, but only when hunger was satiated (EAH). There were no differences by race. These findings provide the first evidence of stress-induced alterations in food intake in a rural, low-income sample of adolescents and point to a strong vulnerability for stress-induced increases in eating in rural boys as well as stress-induced increases in fat intake when satiated as a possible contributor to obesity in youth.

BMI Growth Profiles Among Black Children from Immigrant and US-Born Families.

A large body of research has documented racial/ethnic disparities in childhood obesity in the United States (US) but less work has sought to understand differences within racial groups. Longitudinal studies are needed to describe BMI trajectories across development, particularly for Black children from immigrant families who have been underrepresented in childhood obesity research. The current study utilizes BMI data collected longitudinally from ages 5 to 8 years and growth mixture modeling to (1) identify and visualize growth patterns among Black children from primarily Caribbean immigrant families, and (2) to compare these patterns to growth trajectories among Black children from US-born families. First, we identified four classes or trajectories of growth for Black children from immigrant families. The largest trajectory (70% of the sample) maintained non-overweight throughout the study period. A second trajectory developed overweight by age 8 (25%). Two small trajectory groups demonstrated high rates of moderate and severe obesity-i.e., specifically, a trajectory of accelerated weight gain ending in moderate/severe obesity (3%), and a trajectory of early severe obesity with BMI decreasing slightly with age (2%). We identified a very similar four class/trajectory model among Black children from US-born families, and compared the model to the one for children from immigrant families using multi-group growth mixture modeling. We found that the patterns of growth did not differ significantly between the populations, with two notable exceptions. Among Black children from immigrant families, ∼ 5% were classified into the two heavier BMI trajectories, compared to ∼ 11% of children from US-born families. Additionally, among children with an accelerated weight gain trajectory, children from immigrant families had lower BMIs on average at each time point than children from US-born families. These findings describe the multiple trajectories of weight gain among Black children from immigrant families and demonstrate that although these trajectories are largely similar to those of Black children from US-born families, the differences provide some evidence for lower obesity risk among Black children from immigrant families compared to Black children from US-born families. As this study is the first to describe BMI trajectories for Black children from immigrant families across early and middle childhood, future work is needed to replicate these results and to explore differences in heavier weight trajectories between children from immigrant and US-born families.

Designing a childhood obesity preventive intervention using the multiphase optimization strategy: The Healthy Bodies Project.

BACKGROUND/AIMS: Preventing the development of childhood obesity requires multilevel, multicomponent, comprehensive approaches. Study designs often do not allow for systematic evaluation of the efficacy of individual intervention components before the intervention is fully tested. As such, childhood obesity prevention programs may contain a mix of effective and ineffective components. This article describes the design and rationale of a childhood obesity preventive intervention developed using the multiphase optimization strategy, an engineering-inspired framework for optimizing behavioral interventions. Using a series of randomized experiments, the objective of the study was to systematically test, select, and refine candidate components to build an optimized childhood obesity preventive intervention to be evaluated in a subsequent randomized controlled trial. METHODS: A 24 full factorial design was used to test the individual and combined effects of four candidate intervention components intended to reduce the risk for childhood obesity. These components were designed with a focus on (a) improving children's healthy eating behaviors and nutrition knowledge, (b) increasing physical activity and reducing sedentary activity in the childcare setting, (c) improving children's behavioral self-regulation, and (d) providing parental web-based education to address child target outcomes. The components were tested with approximately 1400 preschool children, ages 3-5 years in center-based childcare programs in Pennsylvania, the majority of which served predominantly Head-Start eligible households. Primary child outcomes included healthy eating knowledge, physical and sedentary activity, and behavioral self-regulation. Secondary outcomes included children's body mass index and appetitive traits related to appetite regulation. RESULTS: Four intervention components were developed, including three classroom curricula designed to increase preschool children's nutrition knowledge, physical activity, and behavioral, emotional, and eating regulation. A web-based parent education component included 18 lessons designed to improve parenting practices and home environments that would bolster the effects of the classroom curricula. A plan for analyzing the specific contribution of each component to a larger intervention was developed and is described. The efficacy of the four components can be evaluated to determine the extent to which they, individually and in combination, produce detectable changes in childhood obesity risk factors. The resulting optimized intervention should later be evaluated in a randomized controlled trial, which may provide new information on promising targets for obesity prevention in young children. CONCLUSION: This research project highlights the ways in which an innovative approach to the design and initial evaluation of preventive interventions may increase the likelihood of long-term success. The lessons from this research project have implications for childhood obesity research as well as other preventive interventions that include multiple components, each targeting unique contributors to a multifaceted problem.

Large Common Mitochondrial DNA Deletions Are Associated with a Mitochondrial SNP T14798C Near the 3' Breakpoints.

Introduction: Large somatic deletions of mitochondrial DNA (mtDNA) accumulate with aging in metabolically active tissues such as the brain. We have cataloged the breakpoints and frequencies of large mtDNA deletions in the human brain. Methods: We quantified 112 high-frequency mtDNA somatic deletions across four human brain regions with the Splice-Break2 pipeline. In addition, we utilized PLINK/Seq to test the association of mitochondrial genotypes with the abundance of these high-frequency mtDNA deletions. A conservative p value threshold of 5E-08 was used to find the significant loci. Results: One mtDNA SNP (T14798C) was significantly associated with mtDNA deletions in two brain regions, the dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus. Since the DLPFC showed the most robust association between T14798C and two deletion breakpoints (7816-14807 and 5462-14807), this association was tested in the DLPFC of a replication sample and validated the first results. Incorporating the C allele at 14,798 bp increased the perfect/imperfect length of the repeat at the 3' breakpoint of the two associated deletions. Conclusion: This is the first study to identify the association of mtDNA SNP with large mtDNA deletions in the human brain. The T14798C allele located in the MT-CYB gene is a common polymorphism that occurs in several mitochondrial haplogroups. We hypothesize that the T14798C association with two deletions occurs by extending the repeat length around the 3' deletion breakpoints. This simple mechanism suggests that mtDNA SNPs can affect the mitochondrial genome structure, especially in brain where high levels of reactive oxygen species lead to deletion accumulation with aging.

Measuring adolescents' eating in the absence of hunger in the home environment using subjective and objective measures.

Eating in the absence of hunger (EAH) has been identified as a behavioral phenotype for obesity. Few studies have reported on objective measures of EAH in adolescents, and fewer yet have objectively measured EAH in a naturalistic, home setting. The purpose of this paper was to examine relations between objective, adolescent-report and parent-report measures of EAH, and to examine variation by sex and race. Participants included 295 predominantly low-income and rural adolescents (mean age = 14.2 ± 0.6 years) and their parents, drawn from the Family Life Project. An EAH task was administered in the home following an ad-libitum meal and compulsory milkshake; EAH was also reported on a web-based survey (both adolescent and parent reports) and adolescents' BMIz was calculated from height and weight, measured in the home or self-reported on the web survey. A high degree of variability in EAH intake was observed (range = 8-741 kcals). Parent and adolescent reports of EAH were weakly correlated and unrelated to observed EAH consumption; only adolescent reports of EAH were related to their BMIz. Several relations varied by sex and race. Positive associations between reported and observed EAH was only observed in girls, and positive associations between observed EAH and BMI was only observed in boys and in white adolescents. Overall EAH consumption was significantly greater in boys and in white adolescents. These findings suggest that EAH can be measured in adolescents in the home. In this sample of youth experiencing rural poverty, this home-based measure appears most valid for white adolescent girls.

Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder.

Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.

Profiles of Behavioral Self-Regulation and Appetitive Traits in Preschool Children: Associations With BMI and Food Parenting Practices.

Appetitive traits that contribute to appetite self-regulation have been shown to relate to non-food-related regulation in general domains of child development. Latent profile analysis (LPA) was used to identify typologies of preschool children's behavioral self-regulation (BSR) and appetitive traits related to appetite self-regulation (ASR), and we examined their relation with children's BMIz and food parenting practices. Participants included 720 children and their parents (90% mothers), drawn from the baseline assessment of a childhood obesity preventive intervention. BSR measures included teacher reports of children's inhibitory control, impulsivity and attentional focusing, as well as an observed measure of inhibitory control. ASR was assessed using parents' reports of children's appetitive traits related to food avoidance (e.g., satiety responsiveness, slowness in eating) and food approach (e.g., enjoyment of food, food responsiveness). Children's body mass index z-score (BMIz) was calculated from measured height and weight. Parents' BMI and food parenting practices were also measured. Four profiles were identified that characterized children with dysregulated behavior, higher food approach and lower food avoidance (16%), dysregulated behavior but lower food approach and higher food avoidance (33%), regulated behavior but highest food approach and lowest food avoidance (16%), and highly-regulated behavior, lowest food approach and highest food avoidance (35%). Children's BMIz was highest in the profile consisting of children with dysregulated behavior, higher food approach and lower food avoidance. BMI was similar in the profile with children with regulated behavior but highest food approach and lowest food avoidance; children in this profile also had parents who reported the highest levels of controlling food parenting practices, and the lowest levels of parental modeling of healthy eating. Compared to all other profiles, children in the profile characterized by highly-regulated behavior, lowest food approach and highest food avoidance had the lowest BMIz and had parents who reported food parenting practices characterized by the highest levels of child control in feeding and the lowest levels of pressure to eat. These findings provide evidence of differing patterns of relations between self-regulation across behavioral and eating domains, and children's obesity risk may vary based on these different patterns.

Family Psychosocial Assets, Child Behavioral Regulation, and Obesity.

BACKGROUND AND OBJECTIVES: Little attention has been given to the study of early childhood factors that protect against the development of obesity and severe obesity. We investigated whether exposure to familial psychosocial assets and risks in infancy (1-15 months) and early childhood (24-54 months) and child behavioral regulation in early childhood predict longitudinal change in BMI (2 to 15 years). METHODS: Participants included 1077 predominantly non-Hispanic, White, English-speaking mother-child dyads from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development dataset. Cumulative familial asset and risk indices were created using measures (eg, maternal parenting sensitivity, poverty) from 2 developmental periods (1-15 months, 24-54 months). A child behavioral regulation index was created on the basis of behavioral tasks and parent reports. Previously published BMI trajectories (nonoverweight [40th percentile], nonoverweight [70th percentile], overweight/obese, severely obese) were used as the outcome. RESULTS: All indices predicted membership in the overweight/obese trajectory; however, when entered into the same model, only familial assets continued to reduce the odds of membership in this trajectory. Familial assets and child behavioral regulation independently reduced the odds of membership in the severely obese trajectory. Furthermore, child behavioral regulation and familial assets buffered the negative effects of familial risk on BMI trajectory membership. CONCLUSIONS: Early exposure to familial assets and child behavioral regulation may have long-term protective effects on weight gain over early exposure to some familial risk factors (eg, poverty); thus, these indices may help foster obesity resilience.

Sorry Parents, Children Consume High Amounts of Candy before and after a Meal: Within-Person Comparisons of Children's Candy Intake and Associations with Temperament and Appetite.

Candy provides little nutritional value and contributes to children's energy intake from added sugars. Factors influencing children's candy intake remain largely unknown. This study describes children's total candy intake (kcal) before and after a meal and examines associations of candy intake in both conditions with children's temperament and appetite among a predominantly White, highly educated sample. Children (n = 38, age 5-8 years) were given free access to 11 candies (5 chocolate, 6 non-chocolate) and non-food alternatives during a pre-meal and a post-meal condition. Parents completed the Child Behavior Questionnaire and the Child Eating Behavior Questionnaire. Total candy intake was less when offered after a meal (209.3 kcal; SD = 111.25) than before a meal when still hungry (283.6 kcal; SD = 167.3), but not statistically different. Individual differences in candy intake between conditions was calculated to categorize children into three groups: "Better Regulators" consumed more candy before a meal (39%), "Consistent/Poorer Regulators" consumed similar amounts before and after a meal regardless of hunger (32%), and "Most Disinhibited" children consumed more candy after a meal when not hungry (29%). The "Better Regulators" group was lowest in negative affect and the "Consistent/Poorer Regulators" group was highest in food responsiveness. Children's candy intake was high relative to daily energy needs both before and after a meal. Child negative affect and food responsiveness appear to be child characteristics that predispose children to poor self-regulation of candy intake before and after a meal.

Preschoolers will drink their GREENS! Children accept, like, and drink novel smoothies containing dark green vegetables (DGVs).

Dark green vegetables (DGVs; e.g., spinach) are a nutrient rich source of essential vitamins and minerals; yet, children's intakes of DGVs fall well below dietary recommendations and creative solutions are needed. This study describes preschoolers (3-5 y) willingness to taste, liking, and intake of fruit-based smoothies containing DGVs (i.e., spinach, collards, kale), commonly referred to as "green smoothies," and explores individual differences in children's eating responses. Using a between-subjects design, preschoolers were randomized to either a FRUIT ONLY smoothie condition (n = 36) or FRUIT+DGV smoothie condition (n = 32). Children's acceptance and intake were collected in one tasting session and one ad libitum snack session, respectively. Parents reported on child food pickiness, food responsiveness, and approach, and children's intake of fruits and DGVs. Children self-reported on previous experience with the study fruits and DGVs. The initial tasting session revealed that the majority of children (84.3%) in the FRUIT+DGV condition willingly tasted all five green smoothies and rated the green smoothies as moderately liked (2.3 ± 0.1). Children in the FRUIT+DGV condition consumed 225.7 ± 31.4 g (9.0 ± 1.3 oz; 1.1 ± 0.2 cups; 91.9 ± 12.9 kcals) of their most preferred green smoothie, providing 18.3 ± 3.7 g (or 0.7 ± 0.1 cups) of DGVs. Children's willingness to try, liking, and intake did not differ by smoothie condition. Individual differences in children's intake are reported. In conclusion, children were willing to try fruit smoothies supplemented with DGVs. Children rated the green smoothies as moderately-liked and children's intake during snack met 31% of their weekly USDA recommendations for DGVs. Adding DGVs to fruit-based smoothies may compliment other effective feeding strategies for increasing children's vegetable consumption.

Off the Charts: Identifying and Visualizing Body Mass Index Trajectories of Rural, Poor Youth.

OBJECTIVES: To identify body mass index (BMI) trajectories using methods and graphing tools that maintain and visualize variability of BMIs ≥95th percentile, and to investigate individual differences in early sociodemographic risk, infant growth and feeding patterns, and maternal weight status among these trajectories. STUDY DESIGN: Participants included 1041 predominantly rural, poor families from the Family Life Project, a longitudinal birth cohort. Youth anthropometrics were measured 8 times between ages 2 months and 12 years. Mothers reported sociodemographic information, infant birth weight, and infant feeding at 2 months and reported child weight and height at 2 months and 12 years. At 6 months, mothers reported breastfeeding. At 2 years, maternal weight and height were measured. RESULTS: Three BMI trajectories were identified: "maintained non-overweight," "developed obesity," and "developed severe obesity." Compared with the non-overweight trajectory, children with heavier trajectories were breastfed for a shorter duration and had heavier mothers at all assessments. The children with the "developed obesity" trajectory were not heavier at birth than those with the non-overweight trajectory, yet they displayed a greater change in weight-for-length percentile during infancy; in addition, their mothers had the greatest change in BMI between 2 months and 12 years. Children with the "developed severe obesity" trajectory were heavier at birth and more likely to have been heavy during infancy and to have been fed solid foods early. CONCLUSIONS: Using informed analytical and graphing approaches, we described patterns of growth, and identified early predictors of obesity and severe obesity trajectories among a diverse sample of rural, poor youth. Researchers are urged to consider these approaches in future work, and to focus on identifying protective factors in youth with obesity and severe obesity.

Executive Function and BMI Trajectories Among Rural, Poor Youth at High Risk for Obesity.

OBJECTIVE: The aim of this study was to identify longitudinal trajectories of conjoint development of executive function (EF) and obesity among a diverse sample of poor, rural youth and to evaluate individual differences in infant growth, parental BMI, and cumulative risk. METHODS: Participants included 948 youth from the Family Life Project. Child anthropometrics were measured at 2 and 6 months and at 2, 3, 4, 5, 7, and 12 years. EF tasks were administered at 3, 4, and 5 years. Mothers reported youth birth weight, parental height and weight, and cumulative risk indicators. RESULTS: Multidimensional growth mixture modeling identified three classes: "High EF - High Obesity Resilience"; "Low EF - Delayed-Onset Severe Obesity"; and "Low EF - Early-Onset Severe Obesity." Youth in the low-EF, early-onset class displayed higher birth weight and BMI at 6 months, whereas the low-EF, delayed-onset class had rapid weight gain during infancy, parents with class II obesity, and greater cumulative risk and was more likely to be Black and female. CONCLUSIONS: Despite increased obesity risk among this sample, the majority of youth exhibited higher EF and some degree of obesity resilience. Youth with EF deficits displayed the greatest risk for severe obesity but had differing BMI trajectories and obesity risk profiles, which has implications for obesity intervention.

Biobehavioral Dysregulation and its Association with Obesity and Severe Obesity Trajectories from 2 to 15 Years of Age: A Longitudinal Study.

OBJECTIVE: This study aimed to identify obesity trajectories from childhood to adolescence (2-15 years of age) and investigate differences in behavioral, eating, and adrenocortical regulation by trajectory membership. METHODS: A total of 1,077 households from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development were included. Anthropometrics were measured 11 times between ages 15 months and 15 years. Behavioral self-regulation was assessed at ages 3 and 4 years. Disordered eating behaviors and awakening cortisol were assessed at age 15 years. RESULTS: Latent growth curve modeling identified four BMI trajectories: two nonoverweight trajectories based on average BMI at the 40th and 70th percentiles and overweight/obesity and severe obesity trajectories. Youth in the severe obesity trajectory exhibited lower behavioral self-regulation in early childhood and lower awakening cortisol at age 15 years compared with youth in the nonoverweight trajectories. Youth in the overweight/obesity and severe obesity trajectories showed higher levels of disordered eating behaviors at age 15 years. CONCLUSIONS: Obesity trajectories were associated with biobehavioral markers of dysregulation in early childhood and adolescence. Dysregulation across biobehavioral domains was particularly apparent among youth who developed severe obesity. Further work is needed to better understand resilience factors that distinguish youth who develop obesity and severe obesity from those who do not.

Parents' and Children's Categorization of Candy are Similar: A Card Sort Protocol.

American children frequently consume candy and, in excess, this may contribute to poor diets with attendant effects on obesity risk. Despite the ubiquity of candy in children's diets, parental concern about children's candy intake, and the diversity of confectionery products available, very little is known about how children and their parents conceptualize candy. Card sorting tasks offer a novel and visual technique to explore and compare an individuals' perceptions of foods and are useful where literacy is limited (e.g. young children). This study aimed to understand and compare how young school-aged children and parents categorize various candy products using a photo card sorting task. In individual laboratory sessions, children (n = 42, 5 to 8 years old) and parents (n = 35) categorized 51 types of candy based on their similarity. A cluster analysis showed that parents created more categories of candies than children (11 versus 8). For example, parents distinguished between candied fruit and candied nuts, whereas children tended to collapse these categories. However, 7 clusters were virtually identical between parents and children (93% similarity). The findings from this study can inform the measurement of candy intake and the development of education materials targeted towards parent feeding around candy.

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder.

Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ (p = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect p ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

Splice-Break: exploiting an RNA-seq splice junction algorithm to discover mitochondrial DNA deletion breakpoints and analyses of psychiatric disorders.

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp 'common deletion' was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns-Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.

Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder.

This study developed potential blood-based biomarker tests for diagnosing and differentiating schizophrenia (SZ), bipolar disorder type I (BD), and normal control (NC) subjects using mRNA gene expression signatures. A total of 90 subjects (n = 30 each for the three groups of subjects) provided blood samples at two visits. The Affymetrix exon microarray was used to profile the expression of over 1.4 million probesets. We selected potential biomarker panels using the temporal stability of the probesets and also back-tested them at two different visits for each subject. The 18-gene biomarker panels, using logistic regression modeling, correctly differentiated the three groups of subjects with high accuracy across the two different clinical visits (83-88% accuracy). The results are also consistent with the actual data and the "leave-one-out" analyses, indicating that the models should be predictive when applied to independent data cohorts. Many of the SZ and BD subjects were taking antipsychotic and mood stabilizer medications at the time of blood draw, raising the possibility that these drugs could have affected some of the differential transcription signatures. Using an independent Illumina data set of gene expression data from antipsychotic medication-free SZ subjects, the 18-gene biomarker panels produced a receiver operating characteristic curve accuracy greater than 0.866 in patients that were less than 30 years of age and medication free. We confirmed select transcripts by quantitative PCR and the nCounter® System. The episodic nature of psychiatric disorders might lead to highly variable results depending on when blood is collected in relation to the severity of the disease/symptoms. We have found stable trait gene panel markers for lifelong psychiatric disorders that may have diagnostic utility in younger undiagnosed subjects where there is a critical unmet need. The study requires replication in subjects for ultimate proof of the utility of the differential diagnosis.

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence.

Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA "common deletion" in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.