Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.
Maternal stress during pregnancy is associated with negative maternal/child outcomes. One potential biomarker of the maternal stress response is cortisol, a product of activity of the hypothalamic-pituitary-adrenal axis. This study evaluated cortisol levels in hair throughout pregnancy as a marker of total cortisol release. Cortisol levels in hair have been shown to be easily quantifiable and may be representative of total cortisol release more than single saliva or serum measures. Hair cortisol provides a simple way to monitor total cortisol release over an extended period of time. Hair cortisol levels were determined from each trimester (15, 26 and 36 wks gestation) and 3 months postpartum. Hair cortisol levels were compared to diurnal salivary cortisol collected over 3 days (3 times/day) at 14, 18, 23, 29, and 34 wks gestational age and 6 wks postpartum from 21 pregnant women. Both salivary and hair cortisol levels rose during pregnancy as expected. Hair cortisol and diurnal salivary cortisol area under the curve with respect to ground (AUCg) were also correlated throughout pregnancy. Levels of cortisol in hair are a valid and useful tool to measure long-term cortisol activity. Hair cortisol avoids methodological problems associated with collection other cortisol measures such as plasma, urine, or saliva and is a reliable metric of HPA activity throughout pregnancy reflecting total cortisol release over an extended period.
The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer’s disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease.
Background Deficient cerebral inhibition is a pathophysiological brain deficit related to poor sensory gating and attention in schizophrenia and other disorders. Cerebral inhibition develops perinatally, influenced by genetic and in utero factors. Amniotic choline activates fetal α7-nicotinic acetylcholine receptors and facilitates development of cerebral inhibition. Increasing this activation may protect infants from future illness by promoting normal brain development. Methods A randomized placebo-controlled clinical trial of dietary phosphatidylcholine supplementation was conducted with 100 healthy pregnant women, who consented to the study at second trimester. Supplementation to twice normal dietary levels for mother or newborn continued through the third postnatal month. All women received dietary advice regardless of treatment. Infants’ electroencephalographic recordings of inhibition of the P50 component of the cerebral evoked response to paired sounds were analyzed. Criterion for inhibition was suppression of the amplitude of the second P50 response by at least half, compared to the first response. Results No adverse effects of choline were observed in maternal health and delivery, birth, or infant development. More choline-treated infants (76%) suppressed the P50 response, compared to placebo-treated infants (43%) at the fifth postnatal week (effect size 0.7). There was no difference at the 13th week. A CHRNA7 genotype associated with schizophrenia diminished P50 inhibition in the placebo-treated infants, but not in the choline-treated infants. Conclusion Neonatal developmental delay in inhibition is associated with attentional problems as the child matures. Perinatal choline activates timely development of cerebral inhibition, even in the presence of gene mutations that otherwise delay it.
OBJECTIVE To investigate the relationships between psychological and physiologic measures of stress, mood and gestational age at delivery and preterm birth (PTB). METHODS This prospective cohort study recruited healthy women in the early second trimester, 18–45 years of age. Validated psychological measures of perceived stress, depressive symptoms, and anxiety were completed at 16, 22, 28, 34 and 40 weeks of gestation. Cortisol concentration was measured in maternal hair at 16, 28, and 40 weeks of gestation to approximate 1st, 2nd, and 3rd trimester levels of physiologic stress. Statistical methods included: analyses of variance (ANOVA), t-tests, Chi-square, Pearson correlations, regression modeling and mediation analysis as appropriate. Hair cortisol concentrations were natural log transformed to normalize values. RESULTS Eleven (12%) out of 90 included women had a spontaneous preterm birth or preterm premature rupture of the membranes. Perceived stress at 16 weeks of gestation correlated with both 2nd trimester cortisol concentration (r= 0.28, p=0.007) and earlier gestational age at delivery (r= −0.30, p< 0.01). Gestational age at delivery was also negatively correlated with cortisol concentration in the 2nd trimester (r= −0.25, p=0.02) and 2nd trimester cortisol concentration was higher in preterm (2.7 ± 0.4 LN pg/mg) vs term (2.0 ± 0.7 LN pg/mg, P<0.001) delivered women. Using mediation statistics, the association between the psychological measure, the physiologic measure, and gestational age at delivery was mainly driven by increased physiologic stress (hair cortisol concentration) in the 2nd trimester (difference in coefficients (standard error)= −0.05(0.02)),. CONCLUSION Higher perceived stress in the 2nd trimester is associated with both elevated 2nd trimester hair cortisol concentration and gestational age at delivery. Physiologic measure of stress in the 2nd trimester appears most strongly associated with preterm birth. Identification and amelioration of early pregnancy stressors may attenuate physiologic stress and ultimately affect preterm birth.
Self-report data from the families of children participating in the San Diego Longitudinal Study of specific developmental language impairment were used to assess familial aggregation in the disorder. Families of impaired children reported higher rates of affected first-degree relatives than did families of matched controls. Significantly higher incidence of maternal and paternal childhood language and/or learning disabilities, as well as sibling disability rates, were reported. The extent to which familial aggregation reflects genetic or environmental influences in specific language disorders remains to be determined.
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