Genomics of body fat percentage may contribute to sex bias in anorexia nervosa

Abstract

Anorexia nervosa (AN) occurs nine times more often in females than in males. Although environmental factors likely play a role, the reasons for this imbalanced sex ratio remain unresolved. AN displays high genetic correlations with anthropometric and metabolic traits. Given sex differences in body composition, we investigated the possible metabolic underpinnings of female propensity for AN. We conducted sex-specific GWAS in a healthy and medication-free subsample of the UK Biobank (n = 155,961), identifying 77 genome-wide significant loci associated with body fat percentage (BF%) and 174 with fat-free mass (FFM). Partitioned heritability analysis showed an enrichment for central nervous tissue-associated genes for BF%, which was more prominent in females than males. Genetic correlations of BF% and FFM with the largest GWAS of AN by the Psychiatric Genomics Consortium were estimated to explore shared genomics. The genetic correlations of BF%_male and BF%_female with AN differed significantly from each other (p < .0001, δ = -0.17), suggesting that the female preponderance in AN may, in part, be explained by sex-specific anthropometric and metabolic genetic factors increasing liability to AN.

Keywords: GWAS; eating disorder; fat-free mass; female; genetic correlation; shared genetics.

Figure 1

Miami plot for female (red), male (blue), and meta‐analyzed (yellow) genome‐wide body fat percentage (BF%) associations. Significant loci from the sex‐combined analyses are highlighted in yellow if they also reached genome‐wide significance in the sex‐specific genome‐wide association studies (GWASs). The genome‐wide significance threshold p < 5 × 10⁻⁸ is represented by the red horizontal lines. Chr = chromosome

Figure 2

Miami plot for female (red), male (blue), and meta‐analyzed (yellow) genome‐wide fat‐free mass (FFM) associations. Significant loci from the sex‐combined analyses are highlighted in yellow if they also reached genome‐wide significance in the sex‐specific genome‐wide association studies (GWASs). The genome‐wide significance threshold p < 5 × 10⁻⁸ is represented by the red horizontal lines. Chr = chromosome

Figure 3

Sex‐specific single nucleotide polymorphism‐based heritability estimates (SNP‐h ²) for body fat percentage and fat‐free mass calculated by BOLT‐LMM (Loh et al., 2015) and linkage disequilibrium score regression (LDSC; Bulik‐Sullivan et al., 2015). Error bars represent SE. All estimated SNP‐h ² were statistically significant

Figure 4

Heatmap of sex‐specific bivariate single nucleotide polymorphism‐based genetic correlations (SNP‐r² _g) of body fat percentage, BMI, fat‐free mass, physical activity, and obesity with AN. The strength of the correlation is reflected in the hue. Blue colors are negative SNP‐r _gs, meaning that the same genetic variants influence both traits in opposite directions, and red are positive SNP‐r _gs meaning that the same genetic variants influence traits in the same direction. Colored squares are significant after correction for multiple comparisons by matrix decomposition and Bonferroni correction (p _Bonferroni = .05/10). The SNP‐r _gs were calculated by linkage disequilibrium score regression (LDSC). AN = anorexia nervosa; BF% = body fat percentage; BMI = body mass index; FFM = fat‐free mass; PA = physical activity; PGC2 = 2nd freeze psychiatric genomics consortium; UKB = UK Biobank

Figure 5

Sex‐specific bivariate single nucleotide polymorphism‐based genetic correlations (SNP‐r _g) of fasting glucose, fasting insulin, and insulin resistance assessed by the HOMA‐IR with AN. The SNP‐r _gs were calculated by linkage disequilibrium score regression (LDSC). Significant SNP‐r _gs are marked with an asterisk (*) after correction for multiple comparisons by matrix decomposition and Bonferroni correction (p _Bonferroni = .05/28). The error bars depict the SE. Summary statistics for BMI‐adjusted HOMA‐IR were not available. AN = anorexia nervosa; BMI = body mass index; HOMA‐IR = insulin resistance by homeostatic model assessment

Figure 6

Sex‐specific bivariate single nucleotide polymorphism‐based genetic correlations (SNP‐r _g) of probable anxiety disorder (anxiety), education years, MDD, neuroticism, OCD, and schizophrenia with anorexia nervosa. The SNP‐r _gs were calculated by linkage disequilibrium score regression (LDSC). Significant SNP‐r _gs are marked with an asterisk (*) after correction for multiple comparisons by matrix decomposition and Bonferroni correction (p _Bonferroni = .05/28). The error bars depict the SE. The SE of the OCD_male reaches above 1 and has been cut off. MDD = major depressive disorder; OCD = obsessive–compulsive disorder