First-Trimester Maternal Serum C-reactive Protein as a Predictor of Third-Trimester Impaired Glucose Tolerance

We evaluated whether first-trimester high-sensitivity C-reactive protein (hsCRP), a suggested marker of pregnancy-associated hyperglycemia, predicts third-trimester impaired glucose tolerance (IGT) in a secondary analysis of a prospective cohort of nondiabetic singletons enrolled at <26 weeks gestation

Genetic Knock-Down of HDAC7 Does Not Ameliorate Disease Pathogenesis in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is an inherited, progressive neurological disorder caused by a CAG/polyglutamine repeat expansion, for which there is no effective disease modifying therapy. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression. Administration of histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) have consistently shown therapeutic potential in models of HD, at least partly through increasing the association of acetylated histones with down-regulated genes and by correcting mRNA abnormalities. The HDAC enzyme through which SAHA mediates its beneficial effects in the R6/2 mouse model of HD is not known. Therefore, we have embarked on a series of genetic studies to uncover the HDAC target that is relevant to therapeutic development for HD. HDAC7 is of interest in this context because SAHA has been shown to decrease HDAC7 expression in cell culture systems in addition to inhibiting enzyme activity. After confirming that expression levels of Hdac7 are decreased in the brains of wild type and R6/2 mice after SAHA administration, we performed a genetic cross to determine whether genetic reduction of Hdac7 would alleviate phenotypes in the R6/2 mice. We found no improvement in a number of physiological or behavioral phenotypes. Similarly, the dysregulated expression levels of a number of genes of interest were not improved suggesting that reduction in Hdac7 does not alleviate the R6/2 HD-related transcriptional dysregulation. Therefore, we conclude that the beneficial effects of HDAC inhibitors are not predominantly mediated through the inhibition of HDAC7

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Abnormal uterine artery Doppler velocimetry predicts adverse outcomes in patients with abnormal analytes.

ObjectivesOur aim was to determine if uterine artery (UtA) Doppler studies would risk-stratify women with abnormal serum analytes on prenatal genetic screening into those at baseline and increased risk for preeclampsia and small-for-gestational age (SGA).Study designThis retrospective cohort study examined outcomes of patients with ⩾one abnormal analyte (PAPP-A&lt;0.3, hCG&gt;3.0, AFP&gt;2.5, inhibin&gt;2.0, or unconjugated estriol&lt;0.3MoM). At approximately 24weeks, we assessed UtA pulsatility index (PI).Main outcome measuresPreeclampsia, preterm preeclampsia, SGA (birthweight (BW) &lt;10%) and intrauterine growth restriction (IUGR) (BW&lt;3%).ResultsWe identified 132 patients with ⩾one abnormal analyte, UtA Doppler screening, and delivery outcomes. Twenty-four (18%) had an elevated UtA PI (PI&gt;1.6); preeclampsia occurred in 16 (12%) and 26 (20%) delivered a SGA neonate. Abnormal UtA Doppler PI increased the likelihood of a composite outcome of preeclampsia or SGA from 27% to 71% (LR 6.48 (2.93, 14.30)); a negative UtA Doppler PI reduced the likelihood to 18% (LR 0.57 (0.42, 0.78)). Abnormal UtA Doppler PI increased the likelihood of a more severe composite outcome of preterm preeclampsia or IUGR from 11% to 39% (LR 5.49 (3.03, 9.97)); a negative UtA Doppler study reduced the likelihood to 4% (LR 0.35 (0.16, 0.80)).ConclusionsIn patients with abnormal serum analytes, abnormal UtA Doppler PI is significantly associated with preeclampsia or SGA and improves the prediction of these adverse outcomes by 9-15-fold. Providers can incorporate UtA Doppler PI into an abbreviated surveillance regimen; they can be reassured that a normal study markedly decreases the risk of a severe early adverse outcome