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

Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Background: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods: We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). Conclusions: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Prevalence and real-world management of NSTEMI with multivessel disease

Background: Non-ST elevation myocardial infarction (NSTEMI) has higher post-discharge mortality than ST-elevation myocardial infarction (STEMI). Prognosis worsens in those with multivessel coronary disease (MVD). However, information about the prevalence and extent of MVD in NSTEMI is limited, in turn limiting insights into optimal treatment strategies. This study aimed to define the prevalence and extent of MVD, preferred treatment strategies and the predictors of MVD in a real-world NSTEMI population. Methods: The Coronary Angiogram Database of South Australia (CADOSA) was used to identify consecutive patients presenting to major teaching hospitals with NSTEMI between 2012 and 2016. Obtaining clinical and angiographic details, patients were stratified by the number of significantly diseased vessels (0,1,2,3-VD), defined by a stenosis of ≥70%, or ≥50% in the left main coronary artery. Data was analysed retrospectively. Results: The prevalence of MVD (2- or 3-VD) was 42% amongst 3,722 NSTEMI presentations. Multivariate logistic regression modelling showed age, male gender, diabetes, dyslipidaemia and prior myocardial infarction predicted MVD over 1-VD or 0-VD. Percutaneous coronary intervention (PCI) was performed in 42% of patients with MVD. This comprised 61% of 2-VD patients and only 22% of 3-VD patients, with 24% and 66% of each group referred for coronary bypass grafting, respectively. Among MVD patients treated with PCI, 76% had their culprit lesion treated alone in the index admission. Conclusions: In this NSTEMI cohort, over 40% had MVD. Notably, a minority of patients with MVD undergoing PCI received multivessel revascularisation. This real-world practice emphasises that further evaluation is required to determine whether complete revascularisation is beneficial in NSTEMI, as reported for STEMI.Angus A. W. Baumann, Rosanna Tavella, Tracy M. Air, Aashka Mishra, Nicholas J. Montarello, Margaret Arstall, Chris Zeitz, Matthew I. Worthley, John F. Beltrame, Peter J. Psalti