Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause lifethreatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved

Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium.

Development Psychopathology in context: famil

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Subfecundity in overweight and obese couples

BACKGROUND: Recent studies indicate that not only women’s but also men’s obesity has adverse effects on fecun-dity and since fecundity is a couple concept, we examined fecundity in relation to overweight and obesity of the couple. We also examined the association between weight changes and fecundity over time. METHODS: Between 1996 and 2002, 64 167 pregnant women enrolled in the Danish National Birth Cohort were interviewed during and 18 months after pregnancy. Information on body mass index (BMI) and waiting time to pregnancy (TTP) was available for 47 835 couples. RESULTS: Among men and women with a BMI of 18.5 kg/m2 or more, we found a dose-response relationship between increasing BMI group and subfecundity (a TTP of more than 12 months): Odds ratio (OR)5 1.32 (95 % CI: 1.26–1.37) for women and OR5 1.19 (95 % CI: 1.14–1.24) for men. Among 2374 women with an initial BMI of 18.5 kg/m2 or more, who participated more than once in the Danish National Birth Cohort, each kilogram increment in weight between the two pregnancies was associated with a 2.84 (95% CI: 1.33–4.35) days longer TTP. CONCLUSIONS: Couples have a high risk of being subfecund if they are both obese. Key words: fecundity/fertility/obesity/overweigh

Prenatal and early life influences on epigenetic age in children: A study of mother-offspring pairs from two cohort studies.

DNA methylation based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. Age acceleration (AA) was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging

Rare and Common Variants Conferring Risk of Tooth Agenesis

To access publisher's full text version of this article click on the hyperlink belowWe present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.Swedish Society of Medicine Swedish Brain Foundation National Institutes of Health (NIH) (National Institute of Dental and Craniofacial Research) Danish National Research Foundation Danish Regional Committees Pharmacy Foundation Egmont Foundation March of Dimes Birth Defects Foundation Health Foundation Novo Nordisk Foundation Oak Foundation fellowship Novo Nordisk Foundation NI