Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Obesity and risk of death or dialysis in younger and older patients on specialized pre-dialysis care

Obesity is associated with increased mortality and accelerated decline in kidney function in the general population. Little is known about the effect of obesity in younger and older pre-dialysis patients. The aim of this study was to assess the extent to which obesity is a risk factor for death or progression to dialysis in younger and older patients on specialized pre-dialysis care.In a multicenter Dutch cohort study, 492 incident pre-dialysis patients (>18y) were included between 2004-2011 and followed until start of dialysis, death or October 2016. We grouped patients into four categories of baseline body mass index (BMI): <20, 20-24 (reference), 25-29, and ≥30 (obesity) kg/m2 and stratified patients into two age categories (<65y or ≥65y).The study population comprised 212 patients younger than 65 years and 280 patients 65 years and older; crude cumulative risk of dialysis and mortality at the end of follow-up were 66% and 4% for patients <65y and 64% and 14%, respectively, for patients ≥65y. Among the <65y patients, the age-sex standardized combined outcome rate was 2.3 times higher in obese than those with normal BMI, corresponding to an excess rate of 35 events/100 patient-years. After multivariable adjustment the hazard ratios (HR) (95% CI) for the combined endpoint by category of increasing BMI were, for patients <65y, 0.92 (0.41-2.09), 1 (reference), 1.76 (1.16-2.68), and 1.81 (1.17-2.81). For patients ≥65y the BMI-specific HRs were 1.73 (0.97-3.08), 1 (reference), 1.25 (0.91-1.71) and 1.30 (0.79-1.90). In the competing risk analysis, taking dialysis as the event of interest and death as a competing event, the BMI-specific multivariable adjusted subdistribution HRs (95% CI) were, for patients <65y, 0.90 (0.38-2.12), 1 (reference), 1.47 (0.96-2.24) and 1.72 (1.15-2.59). For patients ≥65y the BMI-specific SHRs (95% CI) were 1.68 (0.93-3.02), 1 (reference), 1.50 (1.05-2.14) and 1.80 (1.23-2.65).We found that obesity in younger pre-dialysis patients and being underweight in older pre-dialysis patients are risk factors for starting dialysis and for death, compared with those with a normal BMI

Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus