ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: PLoS Genet. 2019; 15(1):e1007603.

This genome wide association study reveals new insights into the genetic basis of thinness by investigating a large cohort of healthy persistently thin individuals. In the past, it has been speculated that inheritance of thinness may constitute a protective factor against environmental factors disposing to obesity (1). Nevertheless, for many years research focused mainly on genetic causes of obesity (2, 3). Recently, some studies led our attention to the lower end of the BMI distribution curve (4–7).

In this comprehensive genome-wide association study (GWAS), genotypes of 1,471 thin healthy individuals, without chronic illness or eating disorder, were compared to individuals with early onset obesity and controls, and were followed up in replication cohorts. Heritability of thinness was shown to be comparable to that of obesity (h2=28.1% vs 32.3%). Higher estimations of heritability in body weight traits had been reported by other study designs (8), although similar heritability estimations have been calculated for body fat (9). The influence of gestational, perinatal and early-childhood factors on weight homeostasis may account for lower than expected heritability (10). The authors generated a standardized genetic risk score (GRS) based on 97 already known BMI-associated loci (2). Each unit GRS-increase was found to lead to a stronger effect among obese populations than among the thin population. Moreover, the authors performed three-way association analyses showing that the established BMI-associated loci explained more phenotypic variance in the obese cohort than in the thin cohort.

The GWAS design enabled the authors to confirm associations of established BMI-associated gene loci (2, 3) in both the obese and thin cohorts, and to report new variants in known loci. Moreover, they found a novel obesity and BMI-associated locus at PKHD1. Importantly, the authors observed that some loci influence either the lower or the upper end of the BMI distribution, while others show effects across the entire distribution. Here, differences between the degrees of obesity and thinness should be taken into account, whereby extreme thinness may not be compatible with life.

These authors provide a solid basis for future genetic studies of thinness, which will be of great importance to further clarify the role of resistance to obesity in an obesogenic environment. Furthermore, as suggested by a later study on gain-of-function MC4R variants (11), knowledge of gene loci and of signaling pathways associated with lower BMI may open the door to new therapeutic strategies against obesity.

References: 1. Costanzo PR, Schiffman SS. Thinness–not obesity–has a genetic component. Neuroscience and Biobehavioral Reviews. 1989;13(1):55–8.

2. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197–206.

3. Berndt SI, Gustafsson S, Magi R, Ganna A, Wheeler E, Feitosa MF, et al. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature Genetics. 2013;45(5):501–12.

4. Whitaker KL, Jarvis MJ, Boniface D, Wardle J. The intergenerational transmission of thinness. Archives of Pediatrics & Adolescent Medicine. 2011;165(10):900–5

5. Bulik CM, Allison DB. The genetic epidemiology of thinness. Obesity Reviews. 2001;2(2):107–15.

6. Zillikens MC, Demissie S, Hsu YH, Yerges-Armstrong LM, Chou WC, Stolk L, et al. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nature Communications. 2017;8(1):80.

7. Ling Y, Galusca B, Hager J, Feasson L, Valsesia A, Epelbaum J, et al. Rational and design of an overfeeding protocol in constitutional thinness: Understanding the physiology, metabolism and genetic background of resistance to weight gain. Annales d’Endocrinologie. 2016;77(5):563–9.

8. Arden NK, Spector TD. Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. Journal of Bone and Mineral Research. 1997;12(12):2076–81.

9. Chu AY, Deng X, Fisher VA, Drong A, Zhang Y, Feitosa MF, et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nature Genetics. 2017;49(1):125–30.

10. Campbell MK. Biological, environmental, and social influences on childhood obesity. Pediatric Research. 2016;79(1-2):205–11.

11. Lotta LA, Mokrosinski J, Mendes de Oliveira E, Li C, Sharp SJ, Luan J, et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell. 2019;177(3):597–607.e9.