Whole genome sequence analysis of a cousin pair with restricting anorexia nervosa

Background Anorexia Nervosa (AN) is a serious mental illness that often has an onset during adolescence. AN is characterized by emaciation, fear of gaining weight despite being underweight, and the highest mortality rate of all psychiatric illnesses. AN is highly heritable and recent meta-analyses in 3,495 anorexia nervosa cases and 10,982 controls has identified a region on chromosome 12 at genome-wide significance, significant common genetic heritability, and genetic correlations with both psychiatric and metabolic traits. AN symptoms and personality traits tend to be present in unaffected family members of the patients, suggesting that certain shared genetic factors within each family may contribute to the unique risk underlying an affected individualu0027s phenotype. Methods To gain insight into the role that unique, family-specific variants may play in the development of AN, we performed whole genome sequencing analysis (Complete Genomics) and extensive annotation of high quality variants (Cypher Genomics, SG-Advisor, ANNOVAR) to search for genetic variants that may influence AN risk in six individuals, consisting of two maternally-linked cousins with severe AN and their parents. We focused on maternally-inherited shared segments; the preferred transmission model for variant filtering was the dominant model. We reviewed results from the Psychiatric Genomic Consortium AN GWAS and other -omic databases at identified genes. Results Of the approximately 5.3 million variants per individual that were analyzed, 494,712 were shared Identical-By-Descent (IBD) by the cousin pair based on maternally derived haplotypes. Based on extensive genetic variant annotations within maternally inherited shared segments, we identified variants in TTC22, MRPS9, DNAJC30, HEPACAM2, USP20, ESF1, and CDK5RAP1. Multiple prediction methods suggest that six of these variants are likely to affect protein function. The region proximal to MRPS9 exhibits an excess of nominally significant findings in the PGC AN GWAS, and eQTLs to MRPS9 and to an uncharacterized antisense gene in many tissues. MRPS9 SNPs are associated in blood with 4-androsten-3beta,17beta-diol disulfate 2 and dehydroisoandrosterone sulfate (a metabolite and a precursor of steroid sex hormones, respectively). Discussion By capitalizing on the homogeneity of the disease presentation and the genomic makeup among two cousins with a diagnosis of restricting-type AN, we exploited whole genome sequence analysis and variant annotation approaches to identify a set of novel variants and genes that may influence AN. Our results suggest that there may be utility in whole genome sequencing of families with affected individuals to detect variants that contribute to a complex disease such as AN.