Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3</jats:p

Mastoid Obliteration Using S53P4 Bioactive Glass in Cholesteatoma Surgery: A 10-Year Single-Center Experience in 173 Adult Patients with Long-Term Magnetic Resonance Imaging Controlled Follow-up

OBJECTIVE: To present the long-term outcomes of mastoid obliteration in cholesteatoma surgery using S53P4 bioactive glass (BAG) in an adult population. STUDY DESIGN: Retrospective cohort study. SETTING: Single-center study. PATIENTS: All 173 adult patients who underwent primary or revision surgery for cholesteatoma with mastoid obliteration using S53P4 BAG with at least 1 year of follow-up including nonecho planar diffusion-weighted magnetic resonance imaging (MRI) (non-EP DWI MRI) and/or second-look surgery to evaluate recidivism. Both canal wall up (CWU) and canal wall down (CWD) procedures were included. INTERVENTIONS: Patients underwent CWU or CWD mastoidectomy using S53P4 BAG. MAIN OUTCOME AND MEASURES: Cholesteatoma recidivism, postoperative complications, Merchant grade, hearing outcome. RESULTS: Cholesteatoma recidivism was assessed by MRI in 97% of all cases and second-look surgery look surgery in 3% of cases. After a mean follow-up period of 53 months, cholesteatoma recidivism was seen in 10% of the cases (n = 18). Using the Kaplan-Meier curve to extrapolate, a 5-year recidivism rate of 12% was estimated. Only minor complications occurred, all resolving spontaneously or after minor treatment. Merchant grade of 0 to 1 was achieved 95% of the patients, no persistently wet ears were observed. Closure of the air-bone gap within 20 dB was possible in 32%. CONCLUSION: In this long-term (up to 10 yr) follow-up study, we demonstrated the safety of S53P4 BAG. Minimal and only minor postoperative complications were observed. The effectiveness of BAG was indicated by the low rate of recidivism, even when using non-EP DWI MRI, a sensitive and specific noninvasive technique to detect cholesteatoma recidivism