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Effects of Rare Coding Variants in Severe Early-Onset Obesity Genes in the Population-Based UK Biobank Study.

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Τίτλος: Effects of Rare Coding Variants in Severe Early-Onset Obesity Genes in the Population-Based UK Biobank Study.
Συγγραφείς: Jia RY; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK., Lockhart S; University of Cambridge, Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, UK.; Queen's University Belfast, School of Medicine, Dentistry and Biomedical Sciences, Wellcome-Wolfson Institute for Experimental Medicine, Belfast BT9 7BL, UK., Lam BYH; University of Cambridge, Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, UK., Zhao Y; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK., Kentistou KA; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK., Gardner EJ; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK., Farooqi IS; University of Cambridge, Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, UK., O'Rahilly S; University of Cambridge, Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, UK., Day FR; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK., Ong KK; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK.; University of Cambridge, Department of Paediatrics, Cambridge CB2 3RF, UK., Perry JRB; University of Cambridge, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0SL, UK.; University of Cambridge, Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, UK.
Πηγή: The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2025 Oct 16; Vol. 110 (11), pp. e3774-e3782.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375362 Publication Model: Print Cited Medium: Internet ISSN: 1945-7197 (Electronic) Linking ISSN: 0021972X NLM ISO Abbreviation: J Clin Endocrinol Metab Subsets: MEDLINE
Imprint Name(s): Publication: 2017- : New York : Oxford University Press
Original Publication: Springfield, Ill. : Charles C. Thomas
Ιατρικοί όροι (MeSH): Pediatric Obesity*/genetics , Pediatric Obesity*/epidemiology , Obesity, Morbid*/genetics , Obesity, Morbid*/epidemiology, United Kingdom/epidemiology ; Pro-Opiomelanocortin/genetics ; Proprotein Convertase 1/genetics ; Obesity/genetics ; Obesity/epidemiology ; Humans ; Male ; Female ; Biological Specimen Banks ; Body Mass Index ; Adult ; Genetic Predisposition to Disease ; Age of Onset ; Middle Aged ; Penetrance ; Heterozygote ; Exome Sequencing ; Multifactorial Inheritance ; Child ; Loss of Function Mutation ; UK Biobank
Περίληψη: Context: Clinical case-based studies have identified rare pathogenic variants in several genes as causes of severe early-onset obesity, but their penetrance and interaction with polygenic susceptibility in the general population remain unclear.
Objective: We analyzed the United Kingdom Biobank (UKBB) whole-exome sequence data to assess the effects of heterozygous variants in 9 previously reported genes on adult body mass index (BMI) and recalled childhood adiposity.
Methods: Among 419 581 UKBB participants, we identified heterozygous carriers of coding variants that were (1) experimentally characterized as loss of function (LoF), or (2) bioinformatically predicted as rare (minor allele frequency <0.1%) LoF. We assessed variant-level and gene-level population penetrance of obesity and associations with adult BMI and recalled childhood adiposity, and tested the statistical interaction between rare variant carriage and a BMI polygenic score.
Results: Considering experimentally characterized LoF variants (excluding MC4R), we identified 22 heterozygous and 2 homozygous variants in 3 autosomal recessive genes (POMC, PCSK1, LEPR), and 3 autosomal dominant genes (SH2B1, SIM1, KSR2) with at least 10 carriers in the UKBB. Obesity penetrance among carriers ranged from 8% to 29% (median 23%), and none was significantly different from noncarriers (24%, all P > .05). For bioinformatically predicted rare LoF variants, gene-based burden tests showed that carriage of heterozygous variants in MC4R, PCSK1, and POMC was associated with higher adult BMI (effect sizes ranged from 0.5 to 2.5 kg/m2, all P < .003), with no significant interaction effects with common variant polygenic risk of BMI.
Conclusion: This study provides the population-specific report of variant penetrance of known obesity genes and confirmed the heterozygous rare variant effects in MC4R, POMC, and PCSK1. We also underscore the utility of population-based studies in supporting variant classifications.
(© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)
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Grant Information: MC_UU_00006/2 United Kingdom MRC_ Medical Research Council; NIHR Cambridge Comprehensive Biomedical Research Centre
Contributed Indexing: Keywords: obesity; population genetics; variant classifications; whole-exome sequencing
Substance Nomenclature: EC 3.4.21.93 (PCSK1 protein, human)
66796-54-1 (Pro-Opiomelanocortin)
EC 3.4.21.93 (Proprotein Convertase 1)
Entry Date(s): Date Created: 20250304 Date Completed: 20251015 Latest Revision: 20260119
Update Code: 20260130
PubMed Central ID: PMC12527455
DOI: 10.1210/clinem/dgaf132
PMID: 40036808
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1945-7197
DOI:10.1210/clinem/dgaf132