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Study Suggests Both Common SNPs and Rare CNVs May Contribute to Anorexia Risk

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Anorexia nervosa may stem from both common variants and rare copy number changes, according to a recent study appearing in Molecular Psychiatry.

An international research team led by investigators at the Children's Hospital of Philadelphia used a genome-wide association study to assess more than 1,000 individuals with anorexia nervosa and nearly 4,000 unaffected controls. In the process, they turned up several common SNPs — in new and previously implicated genes — that seem to be linked to anorexia nervosa. Their search also turned up a few large, rare CNVs that were found in some individuals with anorexia but not in unaffected controls.

"Our study suggests that both common SNPs and rare CNVs contribute to the pathogenesis of anorexia nervosa," co-corresponding author Hakon Hakonarson, a pediatric researcher affiliated with CHOP and the University of Pennsylvania, said in a statement. "The gene variants we discovered are worthy of further analysis in independent cohorts."

Anorexia nervosa, a mental health problem that's roughly 10 times more common in women than in men, is characterized by symptoms such as an extreme fear of gaining weight, a distorted body image, and refusal to eat sufficient quantities of food, the researchers explained.

Past studies indicate that anorexia is a consequence of both genetic factors that predispose some individuals to the disease as well as certain environmental and/or cultural conditions. But only a few genes — including the delta opioid receptor gene OPRD1 and the serotonin receptor gene HTR1D — have been implicated in anorexia nervosa so far.

"[D]espite various genetic studies that identified a handful of candidate genes associated with [anorexia nervosa], the genetic architecture underlying susceptibility to [anorexia nervosa] has been largely unknown," Hakonarson said in a statement.

In an effort to identify additional genetic factors underlying the disease, the researchers used the Illumina HumanHap610 array to genotype 1,009 women and 24 men who had been diagnosed with anorexia nervosa and 3,733 unaffected pediatric controls.

Although none of the variants identified in the study reached genome-wide significance, the team noted, several SNPs appear to be associated with anorexia nervosa, including a SNP in OPRD1, the opioid receptor linked to anorexia in past studies. Similarly, they found that a variant adjacent to the previously detected HTR1D gene seemed to be linked to a form of anorexia called restricting type anorexia nervosa.

The strongest SNP signal came from a chromosome 7 variant in the gene ZNF804B, the researchers reported, though they also detected potential risk SNPs in and around the cadherin genes CDH9 and CDH10 and the genes AKAP6, NTNG1, and CSRP2BP.

In addition to their search for common variants associated with anorexia nervosa, the team used signal intensity information in their array data to assess CNV patterns in 1,015 individuals with anorexia and 3,532 individuals without anorexia.

While they found that the overall number of CNVs was comparable in the anorexia nervosa cases and controls, the researchers did find some rare CNVs that were present in individuals affected with the disorder but not in the control group.

For instance, they noted, two individuals with anorexia had large, rare deletions affecting a chromosome 13 region containing the neuronally-expressed gene SCAS and other genes. Another two cases had duplications or deletions affecting a region containing the neuronal membrane cell adhesion molecule coding genes CNTN6 and CNTN4.

Nevertheless, the researchers cautioned, additional research is needed to verify the role of the SNPs and CNVs in anorexia nervosa, if any, and to determine the functional consequences of such changes. And, they noted that there are probably additional genetic changes underlying the condition that will only be detected by looking at many more individuals.

"[T]he relatively modest number of anorexia cases explained by these results we found suggests that many other candidate genes remain unknown," Hakonarson said. "Future studies will require much larger sample sizes to detect additional gene variants involved in this complex disorder."

Moreover, the researchers explained, identifying some of the genes and pathways involved in anorexia might require studies that look at genetics within the context of individuals' culture and environment.

"The relative contributions of culture and biology to [anorexia nervosa] have been long debated in this field," the authors noted. "[F]uture association analyses that incorporate cultural background or socioeconomic status may lead to improved power and precision to identify [anorexia nervosa] genes."

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