ArticleThe Journal of clinical endocrinology and metabolism2022
Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution.
Article in The Journal of clinical endocrinology and metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Human Genetics of Adipose Dysfunction: Genomic Mechanisms and Therapeutic Opportunities in Cardiometabolic Disease.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Comprehensive assessment of the genotype-phenotype spectrum and treatment for monoallelic insulin receptoropathy in a cohort of 505 people.Research square · 2026Article
- Integrative exome sequencing and multi-omics analysis elucidates the regulatory role of rare variants in metabolic syndrome.Functional & integrative genomics · 2026Article
- Functional insights into dispensable genes using genome-wide loss-of-function burden tests in Arabidopsis.The Plant cell · 2026Article
- Article
- Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution.American journal of human genetics · 2025Article
- Population-scale gene-based analysis of whole-genome sequencing provides insights into metabolic health.Nature genetics · 2025Article
- Activin Actions in Adipocytes.The Journal of clinical endocrinology and metabolism · 2025Review
- Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease.Genome biology · 2025Article
- Omics Approaches to Study Perilipins and Their Significant Biological Role in Cardiometabolic Disorders.International journal of molecular sciences · 2025Review
- Article
- Human ACVR1C missense variants that correlate with altered body fat distribution produce metabolic alterations of graded severity in knock-in mutant mice.Molecular metabolism · 2024Article
- Genetic Association Between Polycystic Ovary Syndrome and theBiomarker insights · 2024Article
- Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids.Molecular metabolism · 2023Article
- Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The Sexual Dimorphism of Human Adipose Depots.Biomedicines · 2022Review
- Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.Nature communications · 2022Article
- Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity.Nature communications · 2022Article
- Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution.The Journal of clinical endocrinology and metabolism · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
30 authors at 7 institutions in 3 countries.
Funding
Abstract
contextBiological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly noncoding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function (LoF) would be of most therapeutic benefit.
objectiveThis work aimed to identify genes/proteins involved in determining fat distribution.
methodsWe combined the power of genome-wide analysis of array-based rare, nonsynonymous variants in 450 562 individuals in the UK Biobank with exome-sequence-based rare LoF gene burden testing in 184 246 individuals.
resultsThe data indicate that the LoF of 4 genes (PLIN1 [LoF variants, P = 5.86 × 10-7], INSR [LoF variants, P = 6.21 × 10-7], ACVR1C [LoF + moderate impact variants, P = 1.68 × 10-7; moderate impact variants, P = 4.57 × 10-7], and PDE3B [LoF variants, P = 1.41 × 10-6]) is associated with a beneficial effect on body mass index-adjusted waist-to-hip ratio and increased gluteofemoral fat mass, whereas LoF of PLIN4 (LoF variants, P = 5.86 × 10-7 adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B, and ACVR1C favorably affects metabolic phenotypes (eg, triglycerides [TGs] and high-density lipoprotein [HDL] cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes.
conclusionThis study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counterintuitive insight into the potential consequences of targeting these molecules therapeutically.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.