Diversity, compositional and functional differences between gut microbiota of children and adults

The gut microbiota has been shown to play diverse roles in human health and disease although the underlying mechanisms have not yet been fully elucidated. Large cohort studies can provide further understanding into inter-individual differences, with more precise characterization of the pathways by which the gut microbiota influences human physiology and disease processes. Here, we aimed to profile the stool microbiome of children and adults from two population-based cohort studies, comprising 2,111 children in the age-range of 9 to 12 years (the Generation R Study) and 1,427 adult individuals in the range of 46 to 88 years of age (the Rotterdam Study). For the two cohorts, 16S rRNA gene profile datasets derived from the Dutch population were generated. The comparison of the two cohorts showed that children had significantly lower gut microbiome diversity. Furthermore, we observed higher relative abundances of genus Bacteroides in children and higher relative abundances of genus Blautia in adults. Predicted functional metagenome analysis showed an overrepresentation of the glycan degradation pathways, riboflavin (vitamin B2), pyridoxine (vitamin B6) and folate (vitamin B9) biosynthesis pathways in children. In contrast, the gut microbiome of adults showed higher abundances of carbohydrate metabolism pathways, beta-lactam resistance, thiamine (vitamin B1) and pantothenic (vitamin B5) biosynthesis pathways. A predominance of catabolic pathways in children (valine, leucine and isoleucine degradation) as compared to biosynthetic pathways in adults (valine, leucine and isoleucine biosynthesis) suggests a functional microbiome switch to the latter in adult individuals. Overall, we identified compositional and functional differences in gut microbiome between children and adults in a population-based setting. These microbiome profiles can serve as reference for future studies on specific human disease susceptibility in childhood, adulthood and specific diseased populations

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Anti-tissue transglutaminase antibodies (TG2A) positivity and the risk of vitamin D deficiency among children - a cross-sectional study in the generation R cohort

Abstract Background Suboptimal vitamin D status is common in people with celiac disease (CeD), a disease that can be characterized by the presence of serum anti-tissue transglutaminase antibodies (TG2A) (i.e., TG2A positivity). To date, it remains unclear whether childhood TG2A positivity is associated with vitamin D status and how this potential association can be explained by other factors than malabsorption only, since vitamin D is mainly derived from exposure to sunlight. The aim of our study was therefore to assess whether childhood TG2A positivity is associated with vitamin D concentrations, and if so, to what extent this association can be explained by sociodemographic and lifestyle factors. Methods This cross-sectional study was embedded in the Generation R Study, a population-based prospective cohort. We measured serum anti-tissue transglutaminase antibodies (TG2A) concentrations and serum 25-hydroxyvitamin D (25(OH)D) concentrations of 3994 children (median age of 5.9 years). Children with serum TG2A concentrations ≥ 7 U/mL were considered TG2A positive. To examine associations between TG2A positivity and 25(OH)D concentrations, we performed multivariable linear regression, adjusted for sociodemographic and lifestyle factors. Results Vitamin D deficiency (serum 25(OH)D < 50 nmol/L) was found in 17 out of 54 TG2A positive children (31.5%), as compared to 1182 out of 3940 TG2A negative children (30.0%). Furthermore, TG2A positivity was not associated with 25(OH)D concentrations (β -2.20; 95% CI -9.72;5.33 for TG2A positive vs. TG2A negative children), and this did not change after adjustment for confounders (β -1.73, 95% CI -8.31;4.85). Conclusions Our findings suggest there is no association between TG2A positivity and suboptimal vitamin D status in the general pediatric population. However, the overall prevalence of vitamin D deficiency in both populations was high, suggesting that screening for vitamin D deficiency among children, regardless of TG2A positivity, would be beneficial to ensure early dietary intervention if needed

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD