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Articles by Stephen O’Rahilly
Genome-wide mapping of common and rare variant effects on adiposity across childhood
Abstract Our understanding of the genetic architecture of obesity is primarily based on studies of adults, with sparser data from childhood. Here, we conducted age-stratified genetic association studies against objectively measured (n = 62,276) or recalled childhood adiposity-related traits (neff = 599,924), identifying 624 common variants associated with childhood adiposity, with one-third having no concordant association with adult body mass index.
Population-scale gene-based analysis of whole-genome sequencing provides insights into metabolic health - Nature Genetics
Abstract In addition to its coverage of the noncoding genome, whole-genome sequencing (WGS) may better capture the coding genome than exome sequencing. Here we sought to exploit this and identify new rare, protein-coding variants associated with metabolic health in WGS data (n = 708,956) from the UK Biobank and All of Us studies.
Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling | Nature Communications
Abstract Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests.
Humans without GDF15 reassure drug developers - Nature Metabolism
In this issue of Nature Metabolism, nine people lacking growth differentiation factor 15 (GDF15) from conception are shown to be healthy, with normal development and fertility, providing some reassurance about the safety of blocking GDF15 in conditions like cachexia and pregnancy sickness, where GDF15 contributes to disease pathogenesis.
ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis | Proceedings of the National Academy of Sciences
ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis Jérémie Gautheron jeremie.gautheron@inserm.fr, Solaf Elsayed, Valeria Pistorio, +17 , Sam Lockhart, Jamila Zammouri, Martine Auclair, Albert Koulman, Sarah R.
Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease - Nature Genetics
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Abstract Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R.
By Yajie Zhao, Katherine A. Kentistou, Eugene J. Gardner, Katherine Lawler, Felix Day, Lena R. Kaisinger, Hsiao-Jou Cortina Chen, Jaime Berumen-Campos, Pablo Kuri-Morales, Roberto Tapia-Conyer, Jesus Alegre-Díaz, Inês Barroso, Jonathan Emberson, Jason Torres, Katherine Smith, Dirk S. Paul, Florian T. Merkle, Nick Wareham, Slavé Petrovski, Stephen O’Rahilly, Ken Ong
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Nature
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Systemic proteome adaptions to 7-day complete caloric restriction in humans - Nature Metabolism
Abstract 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.
The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 - Scientific Reports
Abstract The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug’s beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production.
Academic clinician–scientists risk becoming an endangered species - Nature Medicine
Barriers to their training and retention threaten medical research Concerns about the future of the clinician–scientist have been expressed for many decades. In 1984, Gordon Gill wrote of ‘the end of the physician scientist’ as he observed academically oriented US doctors move into basic science labs to learn the new techniques of molecular biology1. In the following decades, fewer medical doctors remained active in biomedical science.
Weight loss jabs can cut risk of heart attack or stroke by fifth, study suggests
As part of its Select trial, the company recruited 17,604 adults over the age of 45 from across 41 countries. Each patient had a body mass index (BMI) of 27 or over and established cardiovascular disease, with no history of diabetes. Researchers found that the risk of heart attack or stroke in patients given a 2.4mg once-weekly dose of Wegovy, alongside standard care for the prevention of heart attacks or stroke, reduced by 20% compared with those given a placebo drug.
Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake - Nature Genetics
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Author notes These authors jointly supervised this work: Karen L. Mohlke, Eleanor Wheeler, Stephen O’Rahilly, Daniel J. Fazakerley,Claudia Langenberg. Authors and Affiliations MRC Epidemiology Unit Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK Alice Williamson, Jian’an Luan, Nicholas J.
By Alice Williamson, Anne Jackson, Mette Andersen, Thomas Buchanan, Lee-Ming Chuang, Ren-Hua Chung, Peter Damm, Josée Dupuis, Om P. Dwivedi, Michael R Erdos, Lilian Fernandes Silva, Timothy M Frayling, Christian Gieger, Mark O Goodarzi, Xiuqing Guo, Stefan Gustafsson, Katrin Horn, Chii-Min Hwu, Marcus E Kleber, Timo A Lakka, Allan Linneberg, Ching-Ti Liu, Jian’an Luan, Angela P. Moissl, Andrew Morris, Narisu Narisu, Annette Peters, Rashmi Prasad, Chloé Sarnowski, Markus Scholz, Emma Ahlqvist, Francis Collins, Tove Fall, Leif Groop, Torben Frøstrup Hansen, Heikki A. Koistinen, Markku Laakso, Michael Stumvoll, Johan Sundström, Tiinamaija Tuomi, Robert Wagner, Inês Barroso, Niels Grarup, Michael Boehnke, Nicholas J Wareham, Karen L. Mohlke, Eleanor Wheeler, Stephen O’Rahilly, Daniel J. Fazakerley
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Nature
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Body composition and lung cancer-associated cachexia in TRACERx - Nature Medicine
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Abstract Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC.
By Othman Al-Sawaf, Takahiro Karasaki, Alexander Frankell, Carlos Martinez-Ruiz, Ariana Huebner, Maise Al Bakir, Sophia Ward, Roberto Salgado, Christopher P. Bridge, David C. Christiani, Raymond Mak, Paul Welsh Verified, Ying Liu, Norbert Perrimon, Allan Hackshaw, Stephen O’Rahilly, Nicolai J. Birkbak, TRACERx consortium, Mariam Jamal-Hanjani
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Nature
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The islet’s bridesmaid becomes the bride: Proglucagon-derived peptides deliver transformative therapies
The 2021 Gairdner Prize is awarded to Daniel Drucker, Joel Habener, and Jens Juul Holst for the discovery of novel peptides encoded in the proglucagon sequence and the establishment of their physiological roles. These discoveries underpinned the development of therapeutics that are now benefiting patients with type 2 diabetes and other disorders worldwide.
Obesity therapeutics: The end of the beginning
Obese non-diabetic patients receiving semaglutide, an injectable long-acting GLP-1 receptor agonist, in a large randomized placebo-controlled trial, lost and maintained ∼15% of their body weight for over a year ( ). This impressive result is likely to usher in a new era of anti-obesity drugs based on hormones that suppress food intake, largely through acting on the brain.
“Treasure Your Exceptions”-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture | Diabetes
ADA Award Lectures Abstract The study of humans with genetic mutations which lead to a substantial disturbance of physiological processes has made a contribution to biomedical science that is disproportionate to the rarity of affected individuals. In this lecture, I discuss examples of where such studies have helped to illuminate two areas of human metabolism.
Constitutional Thinness: tALKing the tALK or wALKing the wALK?
In a recent issue of Cell, present a body of data from mice, flies, and humans that suggest (1) a physiological role for Alk in the normal control of energy balance across several species and (2) a possible contribution of genetic variants in or near ALK to the variability of adiposity in humans, more specifically at its lower end.
When two pandemics meet: Why is obesity associated with increased COVID-19 mortality?
Abstract A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19 including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the mechanisms underlying the adverse health consequences of obesity, we present some hypotheses regarding the deleterious impact of obesity on the course of COVID-19.
GDF15-From Biomarker to Allostatic Hormone
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