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Anorexia Nervosa’s complex genetic signature

Computer monitor in STSI/SGM lab shows new sequencing data for the anorexia nervosa study.

While linkage and candidate gene studies have implicated genetic regions and variants that appear to confer susceptibility to anorexia nervosa (AN), scientists have yet to define the genetic basis of the disorder, which has the highest mortality rate of any psychiatric illness.

In addition to enabling valid predictions about a specific patient’s likelihood of developing AN, characterizing the disorder’s genetic underpinnings may reveal new therapeutic targets for drug discovery.

Because of AN’s phenotypic complexity, Scripps Translational Science Institute (STSI) researchers suspect that multiple forms of genetic variation influence the disease’s expression, including the degree to which it is amenable or resistant to treatment. In addition to common single nucleotide and repeat polymorphisms, AN’s genetic contributors could include insertion/deletion variations, copy number variations, inversion polymorphisms and unique de nova single base mutations.

With support from the Price Foundation, STSI scientists are conducting one of the first large-scale candidate gene re-sequencing studies to identify DNA variants involved in any complex neuropsychiatric disease. For re-sequencing, the researchers selected genes that have been previously implicated in AN’s pathogenesis and/or represent known targets for pharmaceuticals with some effectiveness against AN.

STSI scientists sequenced an 800 KB genomic region in about 300 females with AN and 40 women in the control group. To increase the “genetic load” of the DNA samples, the AN group included patients with relatives also affected by the disease.

In this initial targeted sequencing study, STSI researchers hope to identify several genomic regions that are enriched with rare or common genetic variants in patients with AN, but not in the control group of individuals without psychiatric illnesses.

STSI scientists also plan to investigate the neurological complement of the “druggable genome” to search for potential new targets for AN therapy. Because AN is one of the most treatment resistant neuropsychiatric disorders, it may be influenced by undiscovered variants that are outside of traditional serotonin pathways. These undiscovered variants may prove to be useful drug targets.

For more information about research on the genetics of anorexia nervosa: news release about STSI and Children’s Hospital of Philadelphia study published in 2010 in the Molecular Psychiatry journal. The journal paper is titled, “A Genome-wide Association Study on Common SNPs and Rare CNVs in Anorexia Nervosa.”