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1. GDF15 linked to maternal risk of nausea and vomiting during pregnancy

Author

Fejzo, M., Rocha, N., Cimino, I., Lockhart, S. M., Petry, C. J., Kay, R. G., Burling, K., Barker, P., George, A. L., Yasara, N., Premawardhena, A., Gong, S., Cook, E., Rimmington, D., Rainbow, K., Withers, D. J., Cortessis, V., Mullin, P. M., MacGibbon, K. W., Jin, E., Kam, A., Campbell, A., Polasek, O., Tzoneva, G., Gribble, F. M., Yeo, G. S. H., Lam, B. Y. H., Saudek, V., Hughes, I. A., Ong, K. K., Perry, J. R. B., Sutton Cole, A., Baumgarten, M., Welsh, P., Sattar, N., Smith, G. C. S., Charnock-Jones, D. S., Coll, A. P., Meek, C. L., Mettananda, S., Hayward, C., Mancuso, N., and O’Rahilly, S.

Published
2024
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2. MC3R links nutritional state to childhood growth and the timing of puberty

Author

Lam, B. Y. H., Williamson, A., Finer, S., Day, F. R., Tadross, J. A., Gonçalves Soares, A., Wade, K., Sweeney, P., Bedenbaugh, M. N., Porter, D. T., Melvin, A., Ellacott, K. L. J., Lippert, R. N., Buller, S., Rosmaninho-Salgado, J., Dowsett, G. K. C., Ridley, K. E., Xu, Z., Cimino, I., Rimmington, D., Rainbow, K., Duckett, K., Holmqvist, S., Khan, A., Dai, X., Bochukova, E. G., Trembath, R. C., Martin, H. C., Coll, A. P., Rowitch, D. H., Wareham, N. J., van Heel, D. A., Timpson, N., Simerly, R. B., Ong, K. K., Cone, R. D., Langenberg, C., Perry, J. R. B., Yeo, G. S., and O’Rahilly, S.

Published
2021
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5. GDF15 linked to maternal risk of nausea and vomiting during pregnancy

Author

Fejzo, M., primary, Rocha, N., additional, Cimino, I., additional, Lockhart, S. M., additional, Petry, C. J., additional, Kay, R. G., additional, Burling, K., additional, Barker, P., additional, George, A. L., additional, Yasara, N., additional, Premawardhena, A., additional, Gong, S., additional, Cook, E., additional, Rimmington, D., additional, Rainbow, K., additional, Withers, D. J., additional, Cortessis, V., additional, Mullin, P. M., additional, MacGibbon, K. W., additional, Jin, E., additional, Kam, A., additional, Campbell, A., additional, Polasek, O., additional, Tzoneva, G., additional, Gribble, F. M., additional, Yeo, G. S. H., additional, Lam, B. Y. H., additional, Saudek, V., additional, Hughes, I. A., additional, Ong, K. K., additional, Perry, J. R. B., additional, Sutton Cole, A., additional, Baumgarten, M., additional, Welsh, P., additional, Sattar, N., additional, Smith, G. C. S., additional, Charnock-Jones, D. S., additional, Coll, A. P., additional, Meek, C. L., additional, Mettananda, S., additional, Hayward, C., additional, Mancuso, N., additional, and O’Rahilly, S., additional

Published
2023
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9. Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy

Author

Fejzo, M, Rocha, N, Cimino, I, Lockhart, SM, Petry, C, Kay, RG, Burling, K, Barker, P, George, AL, Yasara, N, Premawardhena, A, Gong, S, Cook, E, Rainbow, K, Withers, DJ, Cortessis, V, Mullin, PM, MacGibbon, KW, Jin, E, Kam, A, Campbell, A, Polasek, O, Tzoneva, G, Gribble, FM, Yeo, GSH, Lam, BYH, Saudek, V, Hughes, IA, Ong, KK, Perry, JRB, Sutton Cole, A, Baumgarten, M, Welsh, P, Sattar, N, Smith, GCS, Charnock Jones, DS, Coll, AP, Meek, CL, Mettananda, S, Hayward, C, Mancuso, N, and O’Rahilly, S

Subjects
Article
Abstract

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Published
2023

11. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author

Broadaway, K. A. (K. Alaine), Yin, X. (Xianyong), Williamson, A. (Alice), Parsons, V. A. (Victoria A.), Wilson, E. P. (Emma P.), Moxley, A. H. (Anne H.), Vadlamudi, S. (Swarooparani), Varshney, A. (Arushi), Jackson, A. U. (Anne U.), Ahuja, V. (Vasudha), Bornstein, S. R. (Stefan R.), Corbin, L. J. (Laura J.), Delgado, G. E. (Graciela E.), Dwivedi, O. P. (Om P.), Silva, L. F. (Lilian Fernandes), Frayling, T. M. (Timothy M.), Grallert, H. (Harald), Gustafsson, S. (Stefan), Hakaste, L. (Liisa), Hammar, U. (Ulf), Herder, C. (Christian), Herrmann, S. (Sandra), Hojlund, K. (Kurt), Hughes, D. A. (David A.), Kleber, M. E. (Marcus E.), Lindgren, C. M. (Cecilia M.), Liu, C.-T. (Ching-Ti), Luan, J. (Jian'an), Malmberg, A. (Anni), Moissl, A. P. (Angela P.), Morris, A. P. (Andrew P.), Perakakis, N. (Nikolaos), Peters, A. (Annette), Petrie, J. R. (John R.), Roden, M. (Michael), Schwarz, P. E. (Peter E. H.), Sharma, S. (Sapna), Silveira, A. (Angela), Strawbridge, R. J. (Rona J.), Tuomi, T. (Tiinamaija), Wood, A. R. (Andrew R.), Wu, P. (Peitao), Zethelius, B. (Bjorn), Baldassarre, D. (Damiano), Eriksson, J. G. (Johan G.), Fall, T. (Tove), Florez, J. C. (Jose C.), Fritsche, A. (Andreas), Gigante, B. (Bruna), Hamsten, A. (Anders), Kajantie, E. (Eero), Laakso, M. (Markku), Lahti, J. (Jari), Lawlor, D. A. (Deborah A.), Lind, L. (Lars), Maerz, W. (Winfried), Meigs, J. B. (James B.), Sundstrom, J. (Johan), Timpson, N. J. (Nicholas J.), Wagner, R. (Robert), Walker, M. (Mark), Wareham, N. J. (Nicholas J.), Watkins, H. (Hugh), Barroso, I. (Ines), O'Rahilly, S. (Stephen), Grarup, N. (Niels), Parker, S. C. (Stephen CJ.), Boehnke, M. (Michael), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), Mohlke, K. L. (Karen L.), Broadaway, K. A. (K. Alaine), Yin, X. (Xianyong), Williamson, A. (Alice), Parsons, V. A. (Victoria A.), Wilson, E. P. (Emma P.), Moxley, A. H. (Anne H.), Vadlamudi, S. (Swarooparani), Varshney, A. (Arushi), Jackson, A. U. (Anne U.), Ahuja, V. (Vasudha), Bornstein, S. R. (Stefan R.), Corbin, L. J. (Laura J.), Delgado, G. E. (Graciela E.), Dwivedi, O. P. (Om P.), Silva, L. F. (Lilian Fernandes), Frayling, T. M. (Timothy M.), Grallert, H. (Harald), Gustafsson, S. (Stefan), Hakaste, L. (Liisa), Hammar, U. (Ulf), Herder, C. (Christian), Herrmann, S. (Sandra), Hojlund, K. (Kurt), Hughes, D. A. (David A.), Kleber, M. E. (Marcus E.), Lindgren, C. M. (Cecilia M.), Liu, C.-T. (Ching-Ti), Luan, J. (Jian'an), Malmberg, A. (Anni), Moissl, A. P. (Angela P.), Morris, A. P. (Andrew P.), Perakakis, N. (Nikolaos), Peters, A. (Annette), Petrie, J. R. (John R.), Roden, M. (Michael), Schwarz, P. E. (Peter E. H.), Sharma, S. (Sapna), Silveira, A. (Angela), Strawbridge, R. J. (Rona J.), Tuomi, T. (Tiinamaija), Wood, A. R. (Andrew R.), Wu, P. (Peitao), Zethelius, B. (Bjorn), Baldassarre, D. (Damiano), Eriksson, J. G. (Johan G.), Fall, T. (Tove), Florez, J. C. (Jose C.), Fritsche, A. (Andreas), Gigante, B. (Bruna), Hamsten, A. (Anders), Kajantie, E. (Eero), Laakso, M. (Markku), Lahti, J. (Jari), Lawlor, D. A. (Deborah A.), Lind, L. (Lars), Maerz, W. (Winfried), Meigs, J. B. (James B.), Sundstrom, J. (Johan), Timpson, N. J. (Nicholas J.), Wagner, R. (Robert), Walker, M. (Mark), Wareham, N. J. (Nicholas J.), Watkins, H. (Hugh), Barroso, I. (Ines), O'Rahilly, S. (Stephen), Grarup, N. (Niels), Parker, S. C. (Stephen CJ.), Boehnke, M. (Michael), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), and Mohlke, K. L. (Karen L.)

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value <5×10⁻⁸), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6‐3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6‐3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Published
2023

14. Loss ofMfn1but notMfn2enhances adipogenesis

Author

Mann, JP, primary, Tabara, LC, additional, Alvarez-Guaita, A, additional, Dong, L, additional, Haider, A, additional, Lim, K, additional, Tandon, P, additional, Minchin, JEN, additional, O’Rahilly, S, additional, Patel, S, additional, Fazakerley, DJ, additional, Prudent, J, additional, Semple, RK, additional, and Savage, DB, additional

Published
2022
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15. A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Author

Mann, JP, primary, Duan, X, additional, Alvarez-Guaita, A, additional, Haider, A, additional, Luijten, I, additional, Page, M, additional, Patel, S, additional, Scurria, F, additional, Protasoni, M, additional, Tábara, LC, additional, Virtue, S, additional, O’Rahilly, S, additional, Armstrong, M, additional, Prudent, J, additional, Semple, RK, additional, and Savage, DB, additional

Published
2022
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16. MC3R links nutritional state to childhood growth and the timing of puberty

Author

Lam, BYH, Williamson, A, Finer, S, Day, FR, Tadross, JA, Gonçalves Soares, A, Wade, K, Sweeney, P, Bedenbaugh, MN, Porter, DT, Melvin, A, Ellacott, KLJ, Lippert, RN, Buller, S, Rosmaninho-Salgado, J, Dowsett, GKC, Ridley, KE, Xu, Z, Cimino, I, Rimmington, D, Rainbow, K, Duckett, K, Holmqvist, S, Khan, A, Dai, X, Bochukova, EG, Genes & Health Research Team, Trembath, RC, Martin, HC, Coll, AP, Rowitch, DH, Wareham, NJ, Van Heel, DA, Timpson, N, Simerly, RB, Ong, KK, Cone, RD, Langenberg, C, Perry, JRB, Yeo, GS, O'Rahilly, S, Lam, BYH [0000-0002-3638-9025], Williamson, A [0000-0002-7599-9301], Finer, S [0000-0002-2684-4653], Day, FR [0000-0003-3789-7651], Tadross, JA [0000-0002-8424-1252], Wade, K [0000-0003-3362-6280], Porter, DT [0000-0002-8042-3251], Cimino, I [0000-0003-1397-5408], Holmqvist, S [0000-0001-6709-6666], Khan, A [0000-0002-5189-6906], Martin, HC [0000-0002-4454-9084], Rowitch, DH [0000-0002-0079-0060], Wareham, NJ [0000-0003-1422-2993], van Heel, DA [0000-0002-0637-2265], Timpson, N [0000-0002-7141-9189], Simerly, RB [0000-0001-5840-0152], Ong, KK [0000-0003-4689-7530], Cone, RD [0000-0003-3333-5651], Langenberg, C [0000-0002-5017-7344], Perry, JRB [0000-0001-6483-3771], Yeo, GS [0000-0001-8823-3615], O'Rahilly, S [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, Male, Menarche, Time Factors, Adolescent, Homozygote, Puberty, Hypothalamus, Nutritional Status, Estrous Cycle, Weight Gain, Melanocortins, Mice, Child Development, Phenotype, Animals, Humans, Female, Sexual Maturation, Insulin-Like Growth Factor I, Child, Receptor, Melanocortin, Type 3
Abstract

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Published
2021
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17. An Activating Mutation of AKT2 and Human Hypoglycemia

Author

Hussain, K., Challis, B., Rocha, N., Payne, F., Minic, M., Thompson, A., Daly, A., Scott, C., Harris, J., Smillie, B. J. L., Savage, D. B., Ramaswami, U., De Lonlay, P., O'Rahilly, S., Barroso, I., and Semple, R. K.

Published
2011

18. The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels

Author

Karusheva, Y, primary, Ratcliff, M, additional, Melvin, A, additional, Mörseburg, A, additional, Sattar, N, additional, Barker, P, additional, Burling, K, additional, Backmark, A, additional, Roth, R, additional, Jermutus, L, additional, Guiu-Jurado, E, additional, Blüher, M, additional, Welsh, P, additional, Hyvönen, M, additional, and O’Rahilly, S, additional

Published
2022
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31. WNT10B mutations in human obesity

Author

Christodoulides, C., Scarda, A., Granzotto, M., Milan, G., Dalla Nora, E., Keogh, J., De Pergola, G., Stirling, H., Pannacciulli, N., Sethi, J. K., Federspil, G., Vidal-Puig, A., Farooqi, I. S., O’Rahilly, S., and Vettor, R.

Published
2006
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45. Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort

Author

Wade, KH, primary, Lam, BYH, additional, Melvin, A, additional, Pan, W, additional, Corbin, LJ, additional, Hughes, DA, additional, Rainbow, K, additional, Chen, JH, additional, Duckett, K, additional, Liu, X, additional, Mokrosiński, J, additional, Mörseburg, A, additional, Neaves, S, additional, Williamson, A, additional, Zhang, C, additional, Farooqi, IS, additional, Yeo, GSH, additional, Timpson, NJ, additional, and O’Rahilly, S, additional

Published
2020
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47. GWAS for BMI: a treasure trove of fundamental insights into the genetic basis of obesity

Author

Speakman, Loos, RJF, O'Rahilly, S, Hirschhorn, JN, Allison, DB, Speakman, JR [0000-0002-2457-1823], Loos, RJF [0000-0002-8532-5087], O'Rahilly, S [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
endocrine system diseases, Body Weight, nutritional and metabolic diseases, Humans, Genetic Predisposition to Disease, Obesity, Body Mass Index, Genome-Wide Association Study
Abstract

Muller et al. [1] have provided a strong critique of the Genome-Wide Association Studies (GWAS) of body-mass index (BMI), arguing that the GWAS approach for the study of BMI is flawed, and has provided us with few biological insights. They suggest that what is needed instead is a new start, involving GWAS for more complex energy balance related traits. In this invited counter-point, we highlight the substantial advances that have occurred in the obesity field, directly stimulated by the GWAS of BMI. We agree that GWAS for BMI is not perfect, but consider that the best route forward for additional discoveries will likely be to expand the search for common and rare variants linked to BMI and other easily obtained measures of obesity, rather than attempting to perform new, much smaller GWAS for energy balance traits that are complex and expensive to measure. For GWAS in general, we emphasise that the power from increasing the sample size of a crude but easily measured phenotype outweighs the benefits of better phenotyping.

Published
2018
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48. Dominant negative mutations in human PPAR-gamma associated with severe insulin resistance, diabetes mellitus and hypertension

Author

Barroso, I., Gurnell, M., Crowley, V.E.F., Agostini, M., Schwabe, J.W., Soos, M.A., Maslen, G. Ll, Williams, T.D.M., Lewis, H., Schafer, A.J., Chatterjee, V.K.K., and O'Rahilly, S.

Subjects
Diabetes -- Genetic aspects, Hypertension -- Genetic aspects, Insulin resistance -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

It has been possible to identify the first examples of naturally occurring loss-of-function germline mutations in human PPAR-gamma. There is a strong association between these mutations and an unusual syndrome of strong insulin resistance, early onset diabetes and hypertension. It is possible that residual PPAR-gamma activity, possibly controlled by high endogenous ligand concentrations in adipocytes, is sufficient to maintain adipogenesis. There is a possible causal connection between the PPAR-gamma mutation and early onset hypertension through effects on vascular tone.

Published
1999

50. Genetic architecture of human thinness compared to severe obesity

Author

Riveros-McKay F, Mistry V, Bounds R, Hendricks A, Keogh JM, Thomas H, Henning E, Corbin LJ, Society Scientific Group Understanding, O'Rahilly S, Zeggini E, Wheeler E, Barroso I, and Farooqi IS

Subjects
2. Zero hunger, business.industry, Medicine, Severe obesity, Bioinformatics, business, Genetic architecture, 3. Good health
Published
2019

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