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Genetic architecture of human thinness compared to severe obesity
- Source :
- PLoS Genetics, Vol 15, Iss 1, p e1007603 (2019), Riveros-Mckay, F, Mistry, V, Bounds, R, Hendricks, A, Keogh, J M, Thomas, H, Henning, E, Corbin, L, O'Rahilly, S, Zeggini, E, Wheeler, E & Barroso, I & Sadaf Farooqi, I 2019, ' Genetic architecture of human thinness compared to severe obesity ', PLoS Genetics, vol. 15, no. 1, e1007603 . https://doi.org/10.1371/journal.pgen.1007603, PLoS Genetics
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI [-0.17, -0.82], p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.<br />Author summary Obesity-associated disorders are amongst the leading causes of morbidity and mortality worldwide. Most genome-wide association studies (GWAS) have focused on body mass index (BMI = weight in Kg divided by height squared (m2)) and obesity, but to date no genetic association study testing thin and healthy individuals has been performed. In this study, we recruited a first of its kind cohort of 1,471 clinically ascertained thin and healthy individuals and contrasted the genetic architecture of the trait with that of severe early onset obesity. We show that thinness, like obesity, is a heritable trait with a polygenic component. In a GWAS of persistent healthy thinness vs. severe obesity with a total sample size of 2,927, we are able to find evidence of association in loci that have only been recently discovered using large cohorts with >40,000 individuals. We also find a novel BMI-associated locus at PKHD1 in UK Biobank highlighted by our association study. This work illustrates the value and increased power brought upon by using clinically ascertained extremes to study complex traits and provides a valuable resource on which to study resistance to obesity in an increasingly obesogenic environment.
- Subjects :
- Male
obesity
genome signal processing
Cancer Research
Physiology
Muscle Proteins
Genome-wide association study
QH426-470
Mathematical and Statistical Techniques
0302 clinical medicine
Cell Signaling
Medicine and Health Sciences
Genetics (clinical)
2. Zero hunger
Genetics
0303 health sciences
Statistics
Genomics
Middle Aged
Metaanalysis
ALSPAC
humanities
Neoplasm Proteins
Obesity, Morbid
3. Good health
Physiological Parameters
Physical Sciences
Female
Genomic Signal Processing
childhood obesity
Research Article
Signal Transduction
Adult
human genetics
Receptors, Cell Surface
body mass index
Locus (genetics)
Biology
Research and Analysis Methods
Polymorphism, Single Nucleotide
Childhood obesity
03 medical and health sciences
Thinness
medicine
Humans
Genetic Predisposition to Disease
Statistical Methods
Allele
Molecular Biology
Alleles
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Genetic association
Body Weight
Biology and Life Sciences
Computational Biology
genetic loci
Cell Biology
Heritability
Genome Analysis
medicine.disease
Obesity
Genetic architecture
meta-analysis
genome-wide association studies
Mathematics
030217 neurology & neurosurgery
Genome-Wide Association Study
Transcription Factors
RC
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....93efc9e4475d1cc90958eaab6166b874