Sex-Specific Associations of SNVs rs324981 NPSR1 and rs10914456 HCRTR1 with Eating Disorders in Pakistani Adults: A Case-Control Study

Disordered eating in young adults is shaped by sociocultural pressures and may be modulated by genetic variation. We examined sex differences in eating-pathology, psychosocial correlates, at two candidate loci Hypocretin and Neuropeptide S (HCRTR1 rs10914456; NPSR1 rs324981). A total of 550 individuals visiting various nutrition clinics were initially approached for participation in the study. Of these, 460 consented to take part ,after exclusions, 360 completed SCOFF; 200 scoring >2 proceeded to EAT-26 and comprised the analytic sample (100 males, 100 females). Psychosocial factors (media influence, academic pressure, peer pressure, isolation/loneliness, and K-pop self-comparison) were assessed by a structured questionnaire. EAT-26 total and subscales were compared by sex (t-tests). Genotypes were contrasted by sex using χ² tests; allele frequencies were derived from genotype counts and ORs with CI were computed. Females showed higher EAT-26 total scores than males (29.7±1.9 vs 23.2±1.3; t(198)=2.82, p<0.005); 68% of females and 76% of males scored ≥20. Anorexia subscale scores were greater in females (t(198)=3.713, p<0.0003), as well as binge-eating scores (t(198)=1.722, p<0.05); bulimia indices did not differ by sex (p>0.05). Body dissatisfaction was common (87%) without sex difference (p>0.05).Significant sex associations were observed for media influence (χ²=67.94, p<0.05), academic pressure (χ²=45.6, p<0.0001), K-pop self-comparison (χ²=112.12, p<0.0001), peer pressure (χ²=46.37, p<0.05),and isolation/loneliness (χ²=28.72, p<0.0001).Genotyping data revealed marked sex-dependent associations at both loci. For HCRTR1 rs10914456, female cases showed a significantly higher frequency of the risk (TT) genotype, conferring 4.86-fold greater odds of carrying T-allele relative to males (OR = 4.86, 95% CI: 1.46–16.17, p = 0.001). In contrast, for NPSR1 rs324981, males exhibited a pronounced T-allele–driven risk pattern, being T-carriers (AT+TT) relative to females (OR = 4.11, 95% CI 1.23–13.68, p = 0.022).Within females specifically, the AA genotype was significantly overrepresented compared with T-carrying genotypes (AA vs AT+TT: OR = 3.25, 95% CI: 1.59–6.66, p = 0.0013).Collectively, these results highlight a female-specific recessive risk pattern at HCRTR1 and a male-specific dominant T-allele effect at NPSR1, underscoring robust sex-differentiated genetic susceptibility to disordered eating. Overall females exhibited severe eating-pathology and heightened psychosocial sensitivity than males, while genetic risk showed locus-specific sex patterns. Integrating psychosocial screening with genetic profiling may lead to early intervention.