Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients

Anorexia nervosa (AN) is a common, severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance.(1) Family and twin studies indicate a significant genetic contribution(2,3) and pharmacological data suggest possible dysfunction of the serotonergic(4,5) and dopaminergic(6-9) pathways. Catechol-O-methyltransferase (COMT) is a candidate gene for mediating susceptibility to AN since it is involved in the dopamine catabolism(10) and because its functional polymorphism (Val/Met 158) determines high (H) and low (L) enzymatic activity alleles.(11) Fifty-one Israeli AN patients and their parents were genotyped with the COMT polymorphism. Using the haplotype relative risk (HRR) method it was found that the frequency of the H allele among alleles transmitted to AN patients from their parents was significantly higher than in those not transmitted (68% vs 51% chi (2) = 5.20 df = 1, P = 0.023, odds ratio: 2.01). Transmission disequilibrium test (TDT) revealed that out of 49 heterozygote parents the H allele was transmitted to AN patients 33 times while the L allele was transmitted only 16 (McNemar's chi (2) = 5.90, df = 1, P = 0.015). Our study suggests that the COMT gene is associated with genetic susceptibility to AN, and that individuals homozygous for the high activity allele (HH) have a two-fold increased risk for development of the disorder.