Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

Abstract

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single nucleotide polymorphisms (SNPs) with the lowest p-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI related loci was performed in the AN GWAMA. We detected significant associations (p-values < 5×10−5, Bonferroni corrected p < 0.05) for 9 SNP alleles at 3 independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; poverall: 2.47 × 10−06/pfemales: 3.45 × 10−07/pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet induced obese (DIO) mice as compared to age-matched lean controls. We observed no evidence for associations for the look-up of BMI related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa

“…Clinically, one of the most perplexing features of anorexia nervosa, is how patients’ bodies seem to revert rapidly to a “low set point” after renourishment, which may represent the biological inverse of the reversion to high set points commonly seen in the unsuccessful treatment of obesity (31, 32). As noted by Bulik-Sullivan et al (23) and Hinney et al (33), these observations extend our understanding that the same genetic factors that influence normal variation in BMI, body shape, and body composition may also influence extreme dysregulation of these weight-related features in anorexia nervosa. This pattern of observations complements prior strong evidence for the involvement of neural mechanisms in obesity (34).…”

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

“…In contrast, no associations were found for AN risk, which is consistent with the findings by Brandys et al. (2010), who failed to find a significant effect of a KCTD15 polymorphism previously associated with obesity in AN patients; as well as with several GWAS, which have not identified any KCTD15 SNP related to AN risk (Boraska et al., 2014; Hinney et al., 2017; Wang et al., 2011). In this regard, several loci in or near KCTD15 have repeatedly been associated with obesity in a number of GWAS and replication studies (Mei et al., 2012; Paternoster et al., 2011; Thorleifsson et al., 2009; Willer et al., 2009).…”

A Proposal of the European Association for the Study of Obesity to Improve the ICD-11 Diagnostic Criteria for Obesity Based on the Three Dimensions Etiology, Degree of Adiposity and Health Risk

“…As a consequence of these sex differences, men have a higher risk of metabolic syndrome and cardiovascular disease; after menopause the respective risks increase in females. Genetic factors that sex specifically influence BMI and body fat distribution have been detected [27,28]. …”