Medical conditions in autism spectrum disorders

Autism spectrum disorder (ASD) is a behaviourally defined syndrome where the etiology and pathophysiology is only partially understood. In a small proportion of children with the condition, a specific medical disorder is identified, but the causal significance in many instances is unclear. Currently, the medical conditions that are best established as probable causes of ASD include Fragile X syndrome, Tuberous Sclerosis and abnormalities of chromosome 15 involving the 15q11-13 region. Various other single gene mutations, genetic syndromes, chromosomal abnormalities and rare de novo copy number variants have been reported as being possibly implicated in etiology, as have several ante and post natal exposures and complications. However, in most instances the evidence base for an association with ASD is very limited and largely derives from case reports or findings from small, highly selected and uncontrolled case series. Not only therefore, is there uncertainty over whether the condition is associated, but the potential basis for the association is very poorly understood. In some cases the medical condition may be a consequence of autism or simply represent an associated feature deriving from an underlying shared etiology. Nevertheless, it is clear that in a growing proportion of individuals potentially causal medical conditions are being identified and clarification of their role in etio-pathogenesis is necessary. Indeed, investigations into the causal mechanisms underlying the association between conditions such as tuberous sclerosis, Fragile X and chromosome 15 abnormalities are beginning to cast light on the molecular and neurobiological pathways involved in the pathophysiology of ASD. It is evident therefore, that much can be learnt from the study of probably causal medical disorders as they represent simpler and more tractable model systems in which to investigate causal mechanisms. Recent advances in genetics, molecular and systems biology and neuroscience now mean that there are unparalleled opportunities to test causal hypotheses and gain fundamental insights into the nature of autism and its development

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

BACKGROUND Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation. CONCLUSION This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from similar to 60 000 individuals in the discovery stage and similar to 90 000 samples in the replication stage.Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels

The role of flavor and fragrance chemicals in TRPA1 (transient receptor potential cation channel, member A1) activity associated with allergies

TRPA1 has been proposed to be associated with diverse sensory allergic reactions, including thermal (cold) nociception, hearing and allergic inflammatory conditions. Some naturally occurring compounds are known to activate TRPA1 by forming a Michael addition product with a cysteine residue of TRPA1 through covalent protein modification and, in consequence, to cause allergic reactions. The anti-allergic property of TRPA1 agonists may be due to the activation and subsequent desensitization of TRPA1 expressed in sensory neurons. In this review, naturally occurring TRPA1 antagonists, such as camphor, 1,8-cineole, menthol, borneol, fenchyl alcohol and 2-methylisoborneol, and TRPA1 agonists, including thymol, carvacrol, 1’S-1’- acetoxychavicol acetate, cinnamaldehyde, α-n-hexyl cinnamic aldehyde and thymoquinone as well as isothiocyanates and sulfides are discussed

Insights into the Synthesis Parameters Effects on the Structural, Morphological, and Magnetic Properties of Copper Oxide Nanoparticles

The present study aims at the integration of the “oxalic conversion” route into “green chemistry” for the synthesis of copper oxide nanoparticles (CuO-NPs) with controllable structural, morphological, and magnetic properties. Two oxalate-containing precursors (H2C2O4.2H2O and (NH4)2C2O4.H2O) and different volume ratios of a mixed water/glycerol solvent were tested. First, the copper oxalates were synthesized and then subjected to thermal decomposition in air at 400 °C to produce the CuO powders. The purity of the samples was confirmed by X-ray powder diffraction (XRPD), and the crystallite sizes were calculated using the Scherrer method. The transmission electron microscopy (TEM) images revealed oval-shaped CuO-NPs, and the scanning electron microscopy (SEM) showed that morphological features of copper oxalate precursors and their corresponding oxides were affected by the glycerol (V/V) ratio as well as the type of C2O42− starting material. The magnetic properties of CuO-NPs were determined by measuring the temperature-dependent magnetization and the hysteresis curves at 5 and 300 K. The obtained results indicate the simultaneous coexistence of dominant antiferromagnetic and weak ferromagnetic behavior

Measurement and genetic architecture of lifetime depression in the Netherlands as assessed by LIDAS (Lifetime Depression Assessment Self-report)

Background Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression. Methods Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS). Results Estimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15–1.32, R2 = 1.47%). Conclusions By assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.</p