New insights into genomic variation in health and disease

A report on the Genomic Disorders conference on Genomic Variation in Health and Disease, Hinxton, UK, 9–11 March, 2009

Occurrence and core-envelope structure of 1--4x Earth-size planets around Sun-like stars

Small planets, 1-4x the size of Earth, are extremely common around Sun-like stars, and surprisingly so, as they are missing in our solar system. Recent detections have yielded enough information about this class of exoplanets to begin characterizing their occurrence rates, orbits, masses, densities, and internal structures. The Kepler mission finds the smallest planets to be most common, as 26% of Sun-like stars have small, 1-2 R_e planets with orbital periods under 100 days, and 11% have 1-2 R_e planets that receive 1-4x the incident stellar flux that warms our Earth. These Earth-size planets are sprinkled uniformly with orbital distance (logarithmically) out to 0.4 AU, and probably beyond. Mass measurements for 33 transiting planets of 1-4 R_e show that the smallest of them, R < 1.5 R_e, have the density expected for rocky planets. Their densities increase with increasing radius, likely caused by gravitational compression. Including solar system planets yields a relation: rho = 2.32 + 3.19 R/R_e [g/cc]. Larger planets, in the radius range 1.5-4.0 R_e, have densities that decline with increasing radius, revealing increasing amounts of low-density material in an envelope surrounding a rocky core, befitting the appellation "mini-Neptunes." Planets of ~1.5 R_e have the highest densities, averaging near 10 g/cc. The gas giant planets occur preferentially around stars that are rich in heavy elements, while rocky planets occur around stars having a range of heavy element abundances. One explanation is that the fast formation of rocky cores in protoplanetary disks enriched in heavy elements permits the gravitational accumulation of gas before it vanishes, forming giant planets. But models of the formation of 1-4 R_e planets remain uncertain. Defining habitable zones remains difficult, without benefit of either detections of life elsewhere or an understanding of life's biochemical origins.Comment: 11 pages, 6 figures, accepted for publication Proc. Natl. Acad. Sc

Prenatal Serum Concentrations of Brominated Flame Retardants and Autism Spectrum Disorder and Intellectual Disability in the Early Markers of Autism Study: A Population-Based Case-Control Study in California.

BackgroundPrior studies suggest neurodevelopmental impacts of polybrominated diphenyl ethers (PBDEs), but few have examined diagnosed developmental disorders.ObjectivesOur aim was to determine whether prenatal exposure to brominated flame retardants (BFRs) is associated with autism spectrum disorder (ASD) or intellectual disability without autism (ID).MethodsWe conducted a population-based case-control study including children with ASD (n=545) and ID (n=181) identified from the California Department of Developmental Services and general population (GP) controls (n=418) from state birth certificates. ASD cases were matched to controls by sex, birth month, and birth year. Concentrations of 10 BFRs were measured in maternal second trimester serum samples stored from routine screening. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses.ResultsGeometric mean concentrations of five of the six congeners with ≥55% of samples above the limit of detection were lower in mothers of children with ASD or ID than in controls. In adjusted analyses, inverse associations with several congeners were found for ASD relative to GP (e.g., quartile 4 vs. 1, BDE-153: AOR=0.56, 95% CI: 0.38, 0.84). When stratified by child sex (including 99 females with ASD, 77 with ID, and 73 with GP), estimates were consistent with overall analyses in boys, but in the opposite direction among girls, particularly for BDE-28 and -47 (AOR=2.58, 95% CI: 0.86, 7.79 and AOR=2.64, 95% CI: 0.97, 7.19, respectively). Similar patterns overall and by sex were observed for ID.ConclusionsContrary to expectation, higher PBDE concentrations were associated with decreased odds of ASD and ID, though not in girls. These findings require confirmation but suggest potential sexual dimorphism in associations with prenatal exposure to BFRs. https://doi.org/10.1289/EHP1079

Improved Cardiorespiratory Fitness Is Associated with Increased Cortical Thickness in Mild Cognitive Impairment

Cortical atrophy is a biomarker of Alzheimer’s disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (V̇O2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. V̇O2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (V̇O2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved V̇O2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI

Exercise Training and Functional Connectivity Changes in Mild Cognitive Empairment and Healthy Elders

Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60–88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

BACKGROUND:The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS:This is the first genetic study of &gt; 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. RESULTS:We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. CONCLUSIONS:Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders

Long-Period Giant Companions to Three Compact, Multiplanet Systems

Understanding the relationship between long-period giant planets and multiple smaller short-period planets is critical for formulating a complete picture of planet formation. This work characterizes three such systems. We present Kepler-65, a system with an eccentric (e = 0.28 ± 0.07) giant planet companion discovered via radial velocities (RVs) exterior to a compact, multiply transiting system of sub-Neptune planets. We also use precision RVs to improve mass and radius constraints on two other systems with similar architectures, Kepler-25 and Kepler-68. In Kepler-68 we propose a second exterior giant planet candidate. Finally, we consider the implications of these systems for planet formation models, particularly that the moderate eccentricity in Kepler-65\u27s exterior giant planet did not disrupt its inner system