Linkage analysis of anorexia nervosa incorporating behavioral covariates

Eating disorders, such as anorexia nervosa (AN) and bulimia nervosa (BN), have genetic and environmental underpinnings. To explore genetic contributions to AN, we measured psychiatric, personality and temperament phenotypes of individuals diagnosed with eating disorders from 196 multiplex families, all accessed through an AN proband, as well as genotyping a battery of 387 short tandem repeat (STR) markers distributed across the genome. On these data we performed a multipoint affected sibling pair (ASP) linkage analysis using a novel method that incorporates covariates. By exploring seven attributes thought to typify individuals with eating disorders, we identified two variables, drive-for-thinness and obsessionality, which delimit populations among the ASPs. For both of these traits, or covariates, there were a cluster of ASPs who have high and concordant values for these traits, in keeping with our expectations for individuals with AN, and other clusters of ASPs who did not meet those expectations. When we incorporated these covariates into the ASP linkage analysis, both jointly and separately, we found several regions of suggestive linkage: one close to genome-wide significance on chromosome 1 (at 210 cM, D1S1660; LOD = 3.46, P = 0.00003), another on chromosome 2 (at 114 cM, D2S1790; LOD = 2.22, P = 0.00070) and a third region on chromosome 13 (at 26 cM, D13S894; LOD = 2.50, P = 0.00035). By comparing our results to those implemented using more standard linkage methods, we find the covariates convey substantial information for the linkage analysis.