Parental overcontrol x OPRM1 genotype interaction predicts school-aged children's sympathetic nervous system activation in response to performance challenge.

Parental overcontrol (OC), the excessive regulation of a child's behavior, cognition, and emotion, is associated with the development of child anxiety. While studies have shown that genetic factors may increase sensitivity to stress, genetic vulnerability to parental OC has not been examined in anxiety etiology. A functional polymorphism in the mu opioid receptor OPRM1 (A118G, rs1799971) has been shown to impact stress reactivity. Using a community sample of children (N = 85, 9-12 years old), we examined the main and interactive effects of maternal OC and child OPRM1 genotype in predicting children's sympathetic nervous system reactivity during a performance stressor. Neither OC nor genotype predicted children's electrodermal activity (EDA); however, the interaction between OC and child genotype significantly predicted stress reactivity, as indexed by EDA, during the challenging task. Among children with the minor G-allele, higher maternal OC was associated with higher reactivity. In A homozygotes, maternal OC was not associated with EDA, suggesting a diathesis-stress pattern of gene x environment interaction. We discuss implications for anxiety etiology and intervention.

Interaction between the Opioid Receptor OPRM1 Gene and Mother-Child Language Style Matching Prospectively Predicts Children's Separation Anxiety Disorder Symptoms.

Recent research suggests that lower mother-child language style matching (LSM) is associated with greater physiological reactivity and insecure attachment in school-aged children, but to date no studies have explored this measure of parent-child behavioral matching for its association with children's anxiety symptoms, a well-known correlate of attachment insecurity and heightened physiological reactivity. There is also considerable evidence of genetic risk for anxiety, including possession of the OPRM1 minor allele, 118G. In the current study (N = 44), we expand upon what is known about children's genetic and environmental risk for anxiety by examining the unique and interactive effects of mother-child LSM and the OPRM1 polymorphism A118G on school-aged children's separation anxiety disorder (SAD) symptoms. SAD symptoms were measured both concurrently with LSM and OPRM1 genotype and two years later through self-report. No significant associations emerged between LSM or OPRM1 and concurrent Time 1 SAD symptoms. However, lower LSM and 118G minor allele possession were both associated with greater SAD symptoms at Time 2; further, the interaction between LSM and OPRM1 genotype significantly predicted SAD symptoms beyond the main effects of the two variables. Possession of the minor allele was only associated with greater SAD symptoms among children in low LSM dyads, whereas children with the minor allele in high LSM dyads showed non-significantly lower SAD symptoms. These findings and a proportion affected analysis provide support for a differential susceptibility model of gene by environment interactions for the OPRM1 gene. We discuss the implications for predicting children's separation anxiety across development.

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol.

Cardiovascular disease (CVD) is the leading cause of death in developed countries. Plasma cholesterol level is a key risk factor in CVD pathogenesis. Genetic and dietary variation both influence plasma cholesterol; however, little is known about dietary interactions with genetic variants influencing the absorption and transport of dietary cholesterol. We sought to determine whether gut expressed variants predicting plasma cholesterol differentially affected the relationship between dietary and plasma cholesterol levels in 1,128 subjects (772/356 in the discovery/replication cohorts, respectively). Four single nucleotide polymorphisms (SNPs) within three genes (APOB, CETP, and NPC1L1) were significantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for gene-by-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with significant findings tested for replication. Novel GxE interactions were identified and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5' of NPC1L1. This study identifies the presence of novel GxE and gender interactions implying that differential gut absorption is the basis for the variant associations with plasma cholesterol. These GxE interactions may account for part of the "missing heritability" not accounted for by genetic associations.

Dietary cholesterol increases paraoxonase 1 enzyme activity.

HDL-associated paraoxonase 1 (PON1) activity has been consistently associated with cardiovascular and other diseases. Vitamins C and E intake have previously been positively associated with PON1 in a subset of the Carotid Lesion Epidemiology and Risk (CLEAR) cohort. The goal of this study was to replicate these findings and determine whether other nutrient intake affected PON1 activity. To predict nutrient and mineral intake values, 1,402 subjects completed a standardized food frequency survey of their dietary habits over the past year. Stepwise regression was used to evaluate dietary and covariate effects on PON1 arylesterase activity. Five dietary components, cholesterol (P < 2.0 × 10(-16)), alcohol (P = 8.51 × 10(-8)), vitamin C (P = 7.97 × 10(-5)), iron (P = 0.0026), and folic acid (0.037) were independently predictive of PON1 activity. Dietary cholesterol was positively associated and predicted 5.5% of PON1 activity, second in variance explained. This study presents a novel finding of dietary cholesterol, iron, and folic acid predicting PON1 activity in humans and confirms prior reported associations, including that with vitamin C. Identifying and understanding environmental factors that affect PON1 activity is necessary to understand its role and that of HDL in human disease.