Increased frequency of rare damaging variants in PLIN4 in patients with anorexia nervosa

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by pathological fear of weight gain, persistent restriction of energy intake, and pervasive body image disturbance. Although AN is substantially heritable, the rare coding variants contributing to susceptibility remain incompletely defined. Pedigree-based whole-exome sequencing studies can help to identify rare, high-effect protein-coding variants and thereby elucidate disease mechanisms.

Whole-exome sequencing was performed on AN-dense family pedigrees to identify candidate genes. The frequency of rare (minor allele frequency <1%), putatively damaging [combined annotation-dependent depletion (CADD) >15, including predicted loss-of-function (LOF)] variants in 32 candidate genes was assessed in 154 unrelated probands of European ancestry. Carrier counts were compared against gnomAD v4 non-Finnish European reference using a TRAPD-style coverage-adjusted denominator (maximum allele number/2 across qualifying sites per gene). Significance was assessed by one-sided Fisher exact test, Bonferroni-corrected across 32 candidate genes.

PLIN4 was the only gene enriched in AN cases at Bonferroni-corrected significance: 17 of 154 patients (11.0%) carried a rare damaging variant versus 3.2% in gnomAD non-Finnish Europeans [odds ratio (OR) 3.86, 95% confidence interval (CI) 2.35 to 6.35; one-sided Fisher p = 9.98e-06; Bonferroni-corrected p = 3.19e-04]. The result is preserved with the index proband removed (n = 153; OR 3.64, 95% CI 2.18 to 6.07; corrected p = 1.13e-03). Six of 154 patients carried predicted LOF variants; 4 of 6 had at least one AN-affected first- or second-degree relative carrying the same variant, providing co-segregation evidence. The LOF-only burden did not survive Bonferroni correction in isolation.

Patients with AN carry a statistically significant excess of rare, putatively damaging variants in PLIN4, at a threshold surviving Bonferroni correction across 32 candidate genes. These findings implicate lipid-droplet biology as a candidate contributor to AN pathophysiology.