Brain-derived neurotrophic factor Val66Met and neuropsychological functioning after early childhood traumatic brain injury.

OBJECTIVE: The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on neuropsychological functioning in children with traumatic brain injury (TBI) relative to orthopedic injury (OI). METHODS: Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Children completed a battery of neuropsychological measures targeting attention, memory, and executive functions at four timepoints spanning the immediate post-acute period to 18 months post-injury. Children also completed a comparable age-appropriate battery of measures approximately 7 years post-injury. Parents rated children's dysexecutive behaviors at all timepoints. RESULTS: Longitudinal mixed models revealed a significant allele status × injury group interaction with a medium effect size for verbal fluency. Cross-sectional models at 7 years post-injury revealed non-significant but medium effect sizes for the allele status x injury group interaction for fluid reasoning and immediate and delayed verbal memory. Post hoc stratified analyses revealed a consistent pattern of poorer neuropsychological functioning in Met carriers relative to Val/Val homozygotes in the TBI group, with small effect sizes; the opposite trend or no appreciable effect was observed in the OI group. CONCLUSIONS: The results suggest a differential effect of the BDNF Val66Met polymorphism on verbal fluency, and possibly fluid reasoning and immediate and delayed verbal memory, in children with early TBI relative to OI. The Met allele-associated with reduced activity-dependent secretion of BDNF-may confer risk for poorer neuropsychological functioning in children with TBI.

Genetic counseling clinic model expansion: Impact on access for general genetics clinic.

Cincinnati Children's Hospital Medical Center (CCHMC) implemented a Genetic Counseling Clinic (GCC), where the appointment for a general genetics indication is conducted solely by a genetic counselor (GC). We conducted a retrospective chart review of 211 patient encounters scheduled in the GCC between January 1, 2022 and June 30, 2022 and collected patient demographics, wait time, appointment characteristics, referral indication, and clinical recommendations. To study impact on patient access, we compared patient demographics and appointment characteristics with 912 patient encounters scheduled in the General Genetics Clinic with a geneticist during the same time period. We found that there were not significant differences in patient demographics scheduled in the GCC as compared with the General Genetics Clinic with the exception of insurance type, where patients scheduled in the GCC were more likely to have private insurance. Patients scheduled in the GCC had a significantly shorter wait time, were more likely to complete their appointment, were more often new to the genetics division, and were more likely to be seen via telehealth (audio plus video or audio-only) as compared with patients scheduled in the General Genetics Clinic. The most common indications for patients scheduled in the GCC were post-test counseling (36.0%) followed by pre-test counseling and coordination of testing (22.3%), and first-line testing for autism, intellectual disability, and developmental delay (13.7%). Completed appointments in the GCC often resulted in the GC ordering genetic testing (67.5%). After genetic testing results were received, most patients (72.7%) did not require subsequent follow-up with the genetics division, thereby reducing burden to the medical genetics team. Our GCC increased access to genetic services and allowed GCs and clinical geneticists to better work at the top of their scope of practice.

Treatment by biomarker-informed endotype vs guideline care in children with difficult-to-treat asthma.

BACKGROUND: Asthma is heterogeneous, contributing to difficulty in disease management. OBJECTIVE: To develop a biomarker-informed treatment model for difficult-to-treat (DTT) asthma and conduct a pilot feasibility study. METHODS: School-aged children (n = 21) with DTT asthma were enrolled and completed 3 medical visits (V1-V3). V2 and V3 were completed approximately 3.5 months and 12 months after V1, respectively. At V1, guideline care and adherence interventions were initiated, and blood samples were collected for asthma biomarker assessment. A personalized treatment algorithm was developed based on biomarkers (treatment by endotype) and was implemented at V2. Asthma outcomes were compared from V1 to V2 (guideline-based care) to V2 to V3 (guideline + biomarker-informed care). RESULTS: Overall retention was 86%. There was an even distribution of participants with allergy, without allergy, and with mixed allergies. The participants received an average of 5.9 interventions (range, 3-9). The allergic phenotype was characterized by increased CDHR3 risk genotype and high transepidermal water loss. High serum interleukin-6 level was most notable in the mixed allergic subgroup. The nonallergic phenotype was characterized by vitamin D deficiency and poor steroid treatment responsiveness. The personalized treatment plans were associated with decreased emergency department visits (median, 1 vs 0; P = .04) and increased asthma control test scores (median, 22.5 vs 23.0; P = .01). CONCLUSION: The biomarker-based treatment algorithm triggered interventions on top of guideline care in all children with DTT asthma studied, supporting the need for this type of multipronged approach. Our findings identify the minimal biomarker set that is informative, reveal that this treatment-by-endotype intervention is feasible and may be superior to guideline care alone, and provide a strong foundation for a definitive trial. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04179461.

Retrospective comparison of parent-reported genetics knowledge, empowerment, and familial uptake of cardiac screening between parents who received genetic counseling by a certified genetic counselor and those who did not: A single US academic medical center study.

Bicuspid aortic valve (BAV) is the most common congenital heart defect, which can cause severe cardiac complications. BAVs cluster in families and demonstrate high heritability. Cardiac screening for first-degree relatives of individuals with a BAV is recommended. This retrospective two-group study evaluated the impact of cardiovascular genetic counseling provided by a board-certified genetic counselor on parent-reported outcomes by comparing parental responses of those who received genetic counseling by a genetic counselor (GC group) for family history of BAV to those who did not (non-GC group). A retrospective chart review from May 2016 to June 2019 identified 133 pediatric patients with an isolated BAV. Parents of eligible probands were invited to complete an online survey assessing genetics knowledge, empowerment (Genomics Outcome Scale), and familial uptake of cardiac screening. Surveys were completed by 38/97 (39%) parents in the non-GC group and 20/36 (56%) parents in the GC group. The median genetics knowledge score was not significantly different between the two groups (GC group: 8, range 3-11 out of a maximum possible of 12; non-GC group: 7, range 2-11; p = .08). The mean empowerment score was not significantly different between the two groups (GC group: mean 24.6, SD 2.2; non-GC group: mean 23.2, SD 3.5; p = .06). The uptake of cardiac screening was significantly higher in the GC group with 39/59 (66%) total first-degree relatives reported as having been screened compared with 36/91 (40%) in the non-GC group (p = .002). Parent-reported outcomes in our study suggest that receiving genetic counseling by a board-certified genetic counselor significantly increased familial uptake of cardiac screening for first-degree relatives of pediatric patients with a BAV. Studies with larger sample sizes are needed to confirm the findings of this study; however, a referral to a genetic counselor should be considered for patients with a BAV.

NAT1 genetic variation increases asthma risk in children with secondhand smoke exposure.

OBJECTIVE: We previously reported that children exposed to secondhand smoke (SHS) that carried variants in the NAT1 gene had over two-fold higher hair cotinine levels. Our objective was to determine if NAT1 polymorphisms confer increased risk for developing asthma in children exposed to SHS. METHODS: White participants in the Cincinnati Childhood Allergy and Air Pollution Study (n = 359) were genotyped for 10 NAT1 variants. Smoke exposure was defined by hair cotinine and parental report. Asthma was objectively assessed by spirometry and methacholine challenge. Findings were replicated in the Genomic Control Cohort (n = 638). RESULTS: Significant associations between 5 NAT1 variants and asthma were observed in the CCAAPS exposed group compared to none in the unexposed group. There was a significant interaction between NAT1 rs13253389 and rs4921581 with smoke exposure (p = 0.02, p = 0.01) and hair cotinine level (p = 0.048, p = 0.042). Children wildtype for rs4921581 had increasing asthma risk with increasing hair cotinine level, whereas those carrying the NAT1 minor allele had an increased risk of asthma regardless of cotinine level. In the GCC, 13 NAT1 variants were associated with asthma in the smoke-exposed group, compared to 0 in the unexposed group, demonstrating gene-level replication. CONCLUSIONS: Variation in the NAT1 gene modifies asthma risk in children exposed to secondhand-smoke. To our knowledge, this is the first report of a gene-environment interaction between NAT1 variants, smoke exposure, cotinine levels, and pediatric asthma. NAT1 genotype may have clinical utility as a biomarker of increased asthma risk in children exposed to smoke.

Mitochondrial replacement therapy: Genetic counselors' experiences, knowledge, and opinions.

Mitochondrial disorders affect at least 1 in 5,000 individuals worldwide and are often incurable and fatal. Mitochondrial replacement therapy (MRT) is an in vitro fertilization technique used to prevent the transmission of mitochondrial disorders. Currently, MRT is the only approach that provides mothers who carry a pathogenic variant in their mitochondrial DNA (mtDNA), the opportunity to have a biological child without a mitochondrial disease. MRT involves the combination of nuclear DNA from the egg of the carrier mother and the cytoplasm from an oocyte donor, which contains healthy mitochondria. While MRT was approved for use in the UK in 2015, the ban on congressional funding for research on 'heritable genetic modification' has made MRT unavailable within the US borders. This survey-based study aimed to describe genetic counselors' experience, knowledge, and opinions about MRT. Additionally, we also assessed whether genetic counselors' comfort discussing MRT with patients, and feelings about clinical use of MRT in the United States changed after providing information about MRT compared with baseline. Responses were received from 139 genetic counselors in North America. Findings indicate low awareness and knowledge about MRT among participants. However, more participants expressed comfort with discussing MRT with patients and more participants were able to form opinions about statements about MRT after they were provided with information about MRT. This study is the first to assess genetic counselors' opinions toward MRT and suggests the need for more education about novel technologies such as MRT among genetic counselors.

Weighing in on asthma: Insights on BMI, magnesium, and hospitalizations from the Ohio Pediatric Asthma Repository.

Objective: Little is known about weight status and its effects on clinical course during hospitalization for asthma exacerbation. We sought to evaluate associations between weight status, specifically body mass index (BMI), with inpatient clinical course and clinical history.Methods: We retrospectively analyzed data from 2012 to 2013 on children hospitalized for asthma exacerbation in a state-wide longitudinal cohort, the Ohio Pediatric Asthma Repository. We examined BMI continuously (z scores) and categorically, comparing overweight and obese (Ov/Ob) to non-overweight and non-obese (nOv/nOb) children. We used linear mixed models controlling for site effects to determine if BMI was related to length of stay, as determined by physiologic readiness for discharge (PRD), defined as time to albuterol spaced every 4 h, need for nonstandard care or clinical history.Results: Across six hospitals, 874 children were included in analyses. BMI was positively associated with PRD (p=.008) but this increase was unlikely to be clinically significant. Ov/Ob children were more likely than nOv/nOb to require nonstandard care with repeat magnesium dosing in intensive care after dosing in the emergency department (OR = 3.23, 95%CI 1.39-7.78). Hospitalization in the year prior to enrollment was positively associated with BMI percentile (73.3 vs. 66.0, p=.028). Sleep disordered breathing was also associated with higher BMI percentile (78.2 vs. 65.9; p=.0013).Conclusions: Ov/Ob children had similar PRD to nOv/nOb children and were prone to repeat magnesium dosing. Previous hospitalization for exacerbation was positively associated with increasing BMI percentile. Additional research should investigate differential magnesium use by weight status, quantifying risks and benefits.

The gendered pay gap in genetic counseling.

A gendered pay gap in the genetic counseling profession has been identified in recent years, though reasons for its existence have not been explored in depth. The primary aim of this study was to determine what demographic characteristics and career experiences influence annual salary rates and which of those factors differ between male and female genetic counselors. The secondary aim of this study was to determine whether genetic counselors perceive a pay gap and to identify attitudes toward their salaries. Surveys were sent to the nearly 4,000 genetic counselors who are members of the National Society of Genetic Counselors (NSGC), and we report results from 355 respondents. A significant interaction was found between gender and position (direct vs. non-direct patient care). In the best-fitting multiple regression model, male genetic counselors earned $23,736 more than females in non-direct patient care roles (p < .001) and $1,552 more than females in direct patient care roles (p < .001). Years of experience, leadership experience score, negotiation attempts, licensure, and certification were all found to be predictors of annual salary. Most female genetic counselors perceived there to be a pay gap and most male genetic counselors did not (p = .01). Results from this study could contribute to changes in employment and compensation practices, as well as impact genetic counselors' strategies in role- and salary-based conversations.

Hydromorphone population pharmacokinetics in pediatric surgical patients.

BACKGROUND: Hydromorphone is an opioid agonist used for pediatric analgesia. Due to lack of data, pediatric dosing (based on adult pharmacokinetic models) is not optimal. AIM: This study characterizes hydromorphone population pharmacokinetics in pediatric surgical patients. METHODS: In this prospective observational study, 34 children (4-18 years, bodyweight 23-89.6 kg) received multiple intravenous hydromorphone boluses followed by postoperative hydromorphone patient-controlled analgesia. Arterial blood samples were collected before and at 3, 10, 30, and 90 (and few samples at 1350) minutes after the first dose. Hydromorphone concentrations were measured by validated LC-MS/MS assay. Nonlinear mixed-effects modeling was used for pharmacokinetic model development. The final population pharmacokinetic model was evaluated by visual predictive check and bootstrap analysis. Monte Carlo simulations based on the final pharmacokinetic model determined optimal patient-controlled analgesia parameters to achieve a target of 20 ng/mL (as the median effective analgesic concentration), using minimum effective analgesic concentration of 4 ng/mL as a proxy for patient-controlled analgesia dose demand, and not exceeding the defined safe upper threshold of 40 ng/mL. RESULTS: Hydromorphone pharmacokinetic profiles were adequately described by a two-compartmental model with first-order elimination. Bodyweight was found to be a significant covariate for hydromorphone clearance. Allometrically scaledpharmacokinetic parameter estimates (per 70 kg), systemic clearance (0.748 L/min), volume of distribution (33 L), peripheral clearance (1.57 L/min), and peripheral volume of distribution (146 L) were similar to reported adult parameter estimates. Sex, race, age, and type of surgery were not identified as significant covariates. To identify optimal patient-controlled analgesia dosing parameters, we simulated several initial loading doses, demand doses, and lockout intervals. Our simulations support an initial patient-controlled analgesia loading dose of 15 µg/kg followed by a demand dose of 6 µg/kg with lockout intervals of 20 minutes. CONCLUSIONS: After intravenous hydromorphone, plasma pharmacokinetic profiles in children undergoing different surgeries were well described by a two-compartment population allometric pharmacokinetic model using bodyweight as the size descriptor. Model informed simulations identified patient-controlled analgesia parameters to inform initial settings, with adjustments as needed based on observed individual effects.

Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome.

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are genetic disorders that affect connective tissue as a result of dysregulated TGF-ß signaling. MFS is most frequently caused by mutations in FBN1 whereas Loeys-Dietz syndrome results from mutations in TGFBR1 or TGFBR2. There is substantial inter- and intra-familial phenotypic variability among these disorders, suggesting the presence of genetic modifiers. Previously, a polymorphism in the TGFßR1 protein termed the TFGBR1*6A allele was found to be overrepresented in patients with MFS and was identified as a low penetrance allele with suggestion as a possible modifier. To further investigate the importance of this variant, a retrospective review of genetic and phenotypic findings was conducted for 335 patients evaluated for suspicion of MFS or related disorders. In patients with a diagnosis of MFS, the presence of the TFGBR1*6A allele was not associated with phenotypic differences. Similarly, careful phenotyping of patients who carried the TFGBR1*6A allele but did not have MFS did not identify an altered frequency of specific connective tissue features. In this small cohort, the results did not reach significance to identify the TFGBR1*6A allele as a major modifier for aortic dilation, ectopia lentis, or systemic features associated with MFS or other connective tissue disorders. © 2016 Wiley Periodicals, Inc.

Influence of Catechol-O-methyltransferase on Executive Functioning Longitudinally After Early Childhood Traumatic Brain Injury: Preliminary Findings.

OBJECTIVE: To elucidate the association of a functional catechol-O-methyltransferase (COMT) genotype (rs4680) with recovery of executive functions up to 18 months after early childhood traumatic brain injury (TBI) compared with an orthopedic injury (OI) group. SETTING: Outpatient. PARTICIPANTS: A total of 134 children with a moderate to severe TBI (n = 63) or OI (n = 71) between the ages of 3 and 6 years who were followed 18 months postinjury. DESIGN: Case-comparison, longitudinal cohort MAIN MEASURES: : The Behavior Rating Inventory of Executive Function, developmental NEuroPSYchological Assessment (NEPSY) of Verbal Fluency, and a modified Stroop Test for young children (Shape School). RESULTS: The low-activity COMT enzyme genotype (AA) was associated with better scores on the developmental NEPSY of Verbal Fluency (F = 3.80; P = .02) and the Shape School (F = 2.89; P = .06) in all participants when controlling for injury type (TBI vs OI) over the first 18 months after injury. Injury type (TBI vs OI) did not significantly moderate the effect of the COMT genotypes on executive function recovery. CONCLUSION: This study provides preliminary evidence for a role of COMT genotypes in long-term recovery of executive function after pediatric TBI and OI. Larger studies are needed to determine the exact link between genetic variation in the COMT gene and TBI recovery in children.

Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma.

BACKGROUND: Epithelial genes have previously been associated with asthma but only explain a small fraction of heritability. In part, this might be due to epistasis, which is often not considered. OBJECTIVE: We sought to determine independent and epistatic associations between filaggrin (FLG), serine protease inhibitor Kazal-type 5 (SPINK5), and thymic stromal lymphopoietin (TSLP) gene variants and childhood asthma. METHODS: Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5, and TSLP in asthmatic, allergic, and nonallergic nonasthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository. Associations with asthma were also assessed in 6 replication populations. RESULTS: We observed independent associations of variants in SPINK5 (P = .003) and TSLP (P = .006) with childhood asthma; a SPINK5 single nucleotide polymorphism was replicated. In subjects with 1 or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated with a significant increase in asthma (67% vs 53%, P = .0017). In contrast, the presence or absence of TSLP minor alleles did not affect asthma risk in subjects without the SPINK5 risk alleles. The SPINK5 and TSLP epistasis was replicated in a black population (P = .036) who did not display independent association with variants in these genes. CONCLUSIONS: Our results support epistasis between SPINK5 and TSLP, which contributes to childhood asthma. These findings emphasize the importance of using biology to inform analyses to identify genetic susceptibility to complex diseases. The results from our study have clinical relevance and support that the therapeutic effects of anti-TSLP therapy in asthmatic patients might be dependent on SPINK5 genotype.

The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries.

Study Objective: To determine if baseline cytokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. Design: Prospective, observational, longitudinal nested study. Setting: University-affiliated quaternary children's hospital. Patients: Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. Measurements: Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and after (up to two weeks) surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score>3/10 beyond 3 months post-surgery) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. Main Results: Analyses included 3,164 measures of 16 cytokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5% female, 59.8% pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (ß=0.95, SE 0.31; p=.003), IL-1ß (ß=0.84, SE 0.36; p=.02), IL-2 (ß=0.78, SE 0.34; p=.03), and IL-12 p70 (ß=0.88, SE 0.40; p=.03) and longitudinal postoperative elevations in GM-CSF (ß=1.38, SE 0.57; p=.03), IFNγ (ß=1.36, SE 0.6; p=.03), IL-1ß (ß=1.25, SE 0.59; p=.03), IL-7 (ß=1.65, SE 0.7, p=.02), and IL-12 p70 (ß=1.17, SE 0.58; p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (ß= -0.39, SE 0.17; p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (ß= -0.57, SE 0.26; p=.03), IL-8 (ß= -0.68, SE 0.24; p=.006), and IL-13 (ß= -0.48, SE 0.22; p=.03). Furthermore, higher odds for CPSP were found for females (vs. males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα, and for pectus (vs. spine) surgery for IL-8 and IL-10. Conclusion: We identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.

The 2019-2020 Dengue Fever Epidemic: Genomic Markers Indicating Severity in Dominican Republic Children.

We performed an observational cohort study to assess associations between genetic factors of dengue fever (DF) severity in children in the Dominican Republic. A total of 488 participants had serologically confirmed DF. We replicated the association between the IFIH1 gene (rs1990760) and severe DF (n = 80/488, p = 0.006) and identified novel associations needing further investigation.

Posterior fossa anomalies diagnosed with fetal MRI: associated anomalies and neurodevelopmental outcomes.

OBJECTIVE: The purpose of this study was to describe the relationship between intracranial and extracranial anomalies and neurodevelopmental outcome for fetuses diagnosed with a posterior fossa anomaly (PFA) on fetal MRI. METHODS: Cases of Dandy-Walker malformation, vermian hypogenesis/hypoplasia, and mega cisterna magna (MCM) were identified through the Fetal Care Center of Cincinnati between January 2004 and December 2010. Parental interview and retrospective chart review were used to assess neurodevelopmental outcome. RESULTS: Posterior fossa anomalies were identified in 59 fetuses; 9 with Dandy-Walker malformation, 36 with vermian hypogenesis/hypoplasia, and 14 with MCM. Cases with isolated PFAs (14/59) had better outcomes than those with additional anomalies (p = 0.00016), with isolated cases of MCM all being neurodevelopmentally normal. Cases with additional intracranial anomalies had a worse outcome than those without intracranial anomalies (p = 0.00017). The presence of extracranial anomalies increased the likelihood of having a poor outcome (p = 0.00014) as did the identification of an abnormal brainstem (p = 0.00018). CONCLUSION: Intracranial and extracranial anomalies were good predictors of neurodevelopmental outcome in this study. The prognosis was poor for individuals with an abnormal brainstem, whereas those with isolated MCM had normal neurodevelopmental outcome.

Brain-Derived Neurotrophic Factor Val66Met and Behavioral Adjustment after Early Childhood Traumatic Brain Injury.

The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on behavioral adjustment in children with traumatic brain injury (TBI) relative to children with orthopedic injury (OI). Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Parents completed the Child Behavior Checklist (CBCL) at the immediate post-acute period, 6, 12, and 18 months after injury, and an average of 3.5 and 7 years after injury. Longitudinal mixed models examined the BDNF Val66Met allele status (Met carriers vs. Val/Val homozygotes) × injury group (TBI vs. OI) interaction in association with behavioral adjustment. After adjusting for continental ancestry, socioeconomic status, time post-injury, and pre-injury functioning, the allele status × injury group interaction was statistically significant for Internalizing, Externalizing, and Total Behavior problems. Post hoc within-group analysis suggested a consistent trend of poorer behavioral adjustment in Met carriers relative to Val/Val homozygotes in the TBI group; in contrast, the opposite trend was observed in the OI group. These within-group differences, however, did not reach statistical significance. The results support a differential effect of the BDNF Val66Met polymorphism on behavioral adjustment in children with early TBI relative to OI, and suggest that the Met allele associated with reduced activity-dependent secretion of BDNF may impart risk for poorer long-term behavioral adjustment in children with TBI.

Systems Biology Guided Gene Enrichment Approaches Improve Prediction of Chronic Post-surgical Pain After Spine Fusion.

OBJECTIVES: Incorporation of genetic factors in psychosocial/perioperative models for predicting chronic postsurgical pain (CPSP) is key for personalization of analgesia. However, single variant associations with CPSP have small effect sizes, making polygenic risk assessment important. Unfortunately, pediatric CPSP studies are not sufficiently powered for unbiased genome wide association (GWAS). We previously leveraged systems biology to identify candidate genes associated with CPSP. The goal of this study was to use systems biology prioritized gene enrichment to generate polygenic risk scores (PRS) for improved prediction of CPSP in a prospectively enrolled clinical cohort. METHODS: In a prospectively recruited cohort of 171 adolescents (14.5 ± 1.8 years, 75.4% female) undergoing spine fusion, we collected data about anesthesia/surgical factors, childhood anxiety sensitivity (CASI), acute pain/opioid use, pain outcomes 6-12 months post-surgery and blood (for DNA extraction/genotyping). We previously prioritized candidate genes using computational approaches based on similarity for functional annotations with a literature-derived "training set." In this study, we tested ranked deciles of 1336 prioritized genes for increased representation of variants associated with CPSP, compared to 10,000 randomly selected control sets. Penalized regression (LASSO) was used to select final variants from enriched variant sets for calculation of PRS. PRS incorporated regression models were compared with previously published non-genetic models for predictive accuracy. RESULTS: Incidence of CPSP in the prospective cohort was 40.4%. 33,104 case and 252,590 control variants were included for association analyses. The smallest gene set enriched for CPSP had 80/1010 variants associated with CPSP (p < 0.05), significantly higher than in 10,000 randomly selected control sets (p = 0.0004). LASSO selected 20 variants for calculating weighted PRS. Model adjusted for covariates including PRS had AUROC of 0.96 (95% CI: 0.92-0.99) for CPSP prediction, compared to 0.70 (95% CI: 0.59-0.82) for non-genetic model (p < 0.001). Odds ratios and positive regression coefficients for the final model were internally validated using bootstrapping: PRS [OR 1.98 (95% CI: 1.21-3.22); ß 0.68 (95% CI: 0.19-0.74)] and CASI [OR 1.33 (95% CI: 1.03-1.72); ß 0.29 (0.03-0.38)]. DISCUSSION: Systems biology guided PRS improved predictive accuracy of CPSP risk in a pediatric cohort. They have potential to serve as biomarkers to guide risk stratification and tailored prevention. Findings highlight systems biology approaches for deriving PRS for phenotypes in cohorts less amenable to large scale GWAS.

Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk.

Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).