Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios.
Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene in a family-based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN-R) and 19 bingeing/purging (AN-BP) subtype] and performed a family-based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN-R and several SNPs in the COMT-ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5-SNP haplotypes in AN-R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT-186C-408G-472G(158Val)-ARVCF-659C(220Pro)-524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN-R patients to their affected daughters, while haplotype A [COMT-186T-408C-472A(158Met)-ARVCF-659T(220Leu)-524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98-6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21-0.70) for AN-R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN-BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli-Jewish population.
Michaelovsky
Elena
E
Felsenstein Medical Research Center, Rabin Medical Center, Petah-Tikva, Israel.
Frisch
Amos
A
Leor
Shani
S
Stein
Daniel
D
Danziger
Yardena
Y
Carel
Cynthia
C
Fennig
Silvana
S
Mimouni
Marc
M
Klauck
Sabine M
SM
Benner
Axel
A
Poustka
Annemarie
A
Apter
Alan
A
Weizman
Abraham
A
D000293:Adolescent; D000328:Adult; D000856:Anorexia Nervosa / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D051186:Armadillo Domain Proteins / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
C411307:ARVCF protein, human; D051186:Armadillo Domain Proteins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; D002394:Catechol O-Methyltransferase