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Study Links Two Gene Variants, One Pathway to Eating Disorder Risk

NEW YORK (GenomeWeb News) – Researchers from the University of Iowa and the University of Texas Southwestern Medical Center have uncovered variants in two related genes that appear to be associated with the risk of developing an eating disorder.

As the researchers reported in the Journal of Clinical Investigation today, they used linkage mapping followed by whole-genome sequencing or whole-exome sequencing to uncover mutations linked to anorexia nervosa or bulimia nervosa in two families with multiple affected members. In one family, the researchers identified a missense mutation in the estrogen-related receptor α, or ESRRA, gene of affected family members, and in the other, they found a missense mutation in the histone deactelyase 4, or HDAC4, gene of affected family members. The proteins those genes encode, the researchers further found, appear to interact.

"If you're considering two randomly discovered genes, the chance that they will interact is small. But, what really sealed the deal for us that the association was real was that the mutations have the same effect," Michael Lutter, an assistant professor of psychiatry at UI and the senior author of the paper, said in a statement.

Anorexia and bulimia affect between 1 percent and 3 percent of women, and about one in 1,000 women die from anorexia. Genetic factors are thought to contribute between half and 80 percent of the risk of developing an eating disorder, though the environment plays a role in disease etiology as well.

To tease out genetic factors, Lutter and his colleagues turned to two large families afflicted by eating disorders to search for rare mutations that may predispose people to the disease.

For the larger of the two families, the researchers used linkage analysis to find a region on chromosome 11 with a high linkage score, higher than any other part of the genome.

To narrow in on rare mutations in the region, the researchers had whole-genome sequencing performed by Complete Genomics on two affected sisters from that family. From that, they identified a guanine-to-adenine missense mutation in the gene ESRRA, which encodes a transcription factor involved in energy balance and metabolism that is upregulated by exercise and calorie restriction in certain tissues. It is also a transcriptional target of the estrogen receptor.

Lutter and his colleagues genotyped the rest of the family, finding that all 10 of the affected family members had this mutation while nine of the 10 unaffected members did not.

An analysis of the second family implicated a different gene. Whole exome-sequencing using Illumina's HiSeq 2000 of five affected family members and three unaffected members found six mutations on chromosome 2 that co-segregated with disease. Only one, though, a cytosine-to- thymine missense mutation in HDAC, was predicted to affect protein functions by PolyPhena and SIFT.

HDAC, the researchers noted, is a transcription repressor known to be involved in movement, body weight homeostasis, and neuronal plasticity.

Both ESRRA and HDAC4, though, have been implicated in similar processes, like cardiac formation and converting muscle fibers from glycotic to oxidative. That and other factors lead Lutter and his colleagues to suspect that they may both act in a biological pathway that may predispose people to eating disorders.

In HeLa cells and then in mouse cortex cells, the researchers expressed wild-type versions of the two genes and found using immunoprecipitation and western blotting that the ESRRA and HDAC4 interacted. In addition, when they expressed mutated versions of the genes in the cell lines, they found that the proteins still interacted.

Further, by examining mRNA levels in HeLa cells, Lutter and his colleagues found that HDAC4 represses ESRRA activity, affecting downstream ESRRA targets. In addition, expression of the ESRRA variant the researchers uncovered in the first family reduced the number of target genes the protein activated as compared to wild-type ESRRA. Similarly, expression of the HDAC4 mutation found in the second family increased repression of ESRRA target genes as compared to wild-type HDAC4. That is, the researchers reported, both mutations decrease the expression of ESRRA target genes

"The fact that the HDAC4 mutation happens to increase the gene activity and happens to increase its ability to repress the ESSRA protein we found in the other family was just beyond coincidence," Lutter added.

The researchers also speculated that estrogen signaling might mediate eating disorder risk, noting that anorexia and bulimia disproportionately affect women. Both ESRRA and HDAC4 proteins have estrogen receptor α binding sites, and estrogen has previously been shown to affect ESRRA expression, they noted.

According to UI, the researchers plan to study whether there are genes involved in this pathway that may contribute to eating disorder risk as well as whether there are any small molecules targeting those genes that could be developed into therapies for eating disorders.