BackgroundPrenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol’s effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date.MethodsGenome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip.ResultsAfter correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders.ConclusionsThese findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0074-4) contains supplementary material, which is available to authorized users.

Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome. It contributes significantly to infant mortality and has serious implications in adult cardiology. Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified. In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 well-phenotyped controls. 73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort. After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci. Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases. Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis. In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level. Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.

Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared to the general population. Here, we evaluated the impact of somatic mosaic chromosomal alterations (mCAs) on death of CVD causes, coronary artery disease (CAD) causes, from cancer, and of any cause in patients with a cancer diagnosis within the UK Biobank (n=48 919). mCAs were derived from DNA genotyping array intensity data and long-range chromosomal phase inference from participants. Overall, 10 070 individuals (20.6%) carried ≥1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.09-1.71, P=0.006), from cancer (HR: 1.06, 95% CI: 1.00-1.11, P=0.041), and death of any cause (HR: 1.07, 95% CI: 1.02-1.12, P=0.005). Among cancer survivors, carriers of any mCA are at an increased risk of death of CAD causes and of any cause as compared to non-carriers.