sir stephen o'rahilly

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P=0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles …

There is currently no medical therapy to prevent calcific aortic valve stenosis (CAVS). Multi-omics approaches could lead to the identification of novel molecular targets. Here, we perform a genome-wide association study (GWAS) meta-analysis including 14,819 cases among 941,863 participants of European ancestry. We report 32 genomic loci, among which 20 are novel. RNA sequencing of 500 human aortic valves highlights an enrichment in expression regulation at these loci and prioritizes candidate causal genes. Homozygous genotype for a risk variant near TWIST1, a gene involved in endothelial-mesenchymal transition, has a profound impact on aortic valve transcriptomics. We identify five genes outside of GWAS loci by combining a transcriptome-wide association study, colocalization, and Mendelian randomization analyses. Using cross-phenotype and phenome-wide approaches, we highlight the role of …

Background: Growth and differentiation factor 15 (GDF15), a stress-responsive cytokine of the TGFβ superfamily, is also an established regulator of energy homeostasis. The ability of GDF15 to reduce food intake has attracted attention in treating obesity, with several clinical trials ongoing. In addition, GDF15 is elevated in eg, cancer cachexia, chemotherapy-induced anorexia, and morning sickness. However, only a few small studies have investigated the role of GDF15 in anorexia nervosa (AN), a psychiatric disorder characterized by severe weight loss and persistent restriction of food intake.Materials and methods: We analyse the plasma concentration of GDF15 in females with active AN (n= 70), recovered from AN (AN-REC, n= 89), and normal weight, age-matched healthy controls (CTRL, n= 72). Stratified analyses are conducted to explore the association between GDF15 and purging Behaviours. The correlation …

Mutations which perturb leptin-melanocortin signalling are known to cause hyperphagia and obesity but energy expenditure has not been well studied outside rodents. Here we report on a common canine mutation in POMC which prevents production of β-MSH and β-endorphin but not α-MSH; humans, like dogs, produce α-MSH and β-MSH from the POMC pro-peptide but understanding whether the two peptides have independent effects has been difficult because rodents produce only α-MSH. We show energy expenditure is markedly lower in affected dogs which also have increased motivational salience in response to a food cue (increased wanting/hunger). There was no difference in satiety at a modified ad libitum meal or in their hedonic response to food, nor of disruption of ACTH or thyroid axes. In vitro, we show β-MSH signals comparably to α-MSH at melanocortin receptors. These data implicate β-MSH and β-endorphin as important in determining hunger and moderating energy expenditure, and suggest this role is independent of the presence of α-MSH.

Family, twin, and adoption studies have consistently shown that body weight is a highly heritable trait. Genome-wide association studies have identified hundreds of genetic regions or loci containing common variants which are associated with increased body mass index (BMI) or obesity in multiple populations. In addition, disruption of a single gene is sufficient to cause obesity which can present in childhood with or without developmental delay. The discovery and characterization of these monogenic obesity syndromes in mice and humans have paved the way for understanding the molecular framework which underpins weight regulation by establishing a key role for the leptin-melanocortin pathway. Several of these disorders can now be treated with rational mechanism-based therapies. New genetic discoveries continue to provide insights into the links between obesity and disordered behavior and highlight …

Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N= 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P< 5x10− 8) for BP traits, including 113 novel loci. These associations explain~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p= 9.08× 10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P= 9.71× 10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI= 0.781–0.801) to 0.814 (95% CI= 0.805–0.824,∆ AUC= 0.023, P= 2.27 x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.

Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting …

A Woman with Hyperglycemia Refractory to Insulin A 46-year-old woman with type 2 diabetes was admitted to this hospital because of hyperglycemia for which she was receiving over 2000 units of insulin per day. A diagnosis was made.