engleski

WTCCC3 and GCAN: A genomewide association scan of anorexia nervosa

Background: Anorexia nervosa (AN) is a debilitating and potentially life-threatening mental illness. The Genetic Consortium for Anorexia Nervosa (GCAN) is a 20-country consortium dedicated to identifying genes that influence AN. As part of the Wellcome Trust Case Control Consortium 3 (WTCCC3), we conducted the largest genome-wide association study (GWAS) for any eating disorder ever performed. Methods: A GWAS was performed to identify unequivocal evidence of associations between DNA sequence variations and AN. All cases met DSM IV diagnostic criteria for AN (excluding amenorrhea) and were genotyped using the Illumina 660W-Quad array. Genotyping was completed on 2907 AN cases and 14, 860 controls originating from 15 different countries of European ancestry. Controls were carefully selected to match for ancestry of each AN site. Individual association analyses were carried out across 15 strata. Eleven association analyses were conducted per stratum: one with no principal components (PC) adjustment and the others adjusted for up to 10 PCs. On the basis of QQ plots, lambda values and 54 population stratification SNPs, we selected the best analysis per each stratum for the fixed-effects meta-analysis. Only one stratum needed an adjustment for PC1. The genome-wide significance threshold was set to 5x10-8. Results: One SNP on chr5 exceeded genome-wide significance. An additional 94 SNPs, derived from 65 independent signals, had p-values < 10-4. Most of these SNPs are in the frequency and effect size classes expected for common diseases. Replication of SNPs, representing each independent signal, is currently underway in 2400 samples of European origin and 900 Japanese samples. Discussion: For strong/replicated findings, GCAN is well positioned to immediately pursue genomic, transcriptomic, molecular biological, and epidemiological studies in humans. Cross disorder analyses with psychiatric disorders and obesity are planned. Furthermore, functional analysis of human anorexia genes in mice will provide novel insights in the neurobiological mechanisms underlying this perplexing psychiatric disorder.

anorexia nervosa; eating disorders; genetic; GWAS

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