Challenges in Identifying Genetic Contributions to Eating Disorder Risk

Behavioral genetic studies have clearly supported a genetic diathesis to eating disorders, but molecular genetic studies have yet to clearly identify specific genes that increase the risk. This likely reflects the early stage of molecular genetic research in this area as well as the etio- logic complexity of the disorders. As with most psychiatric disorders, the genetic diathesis to eating disorders is likely to involve complex inheritance rather than Mendelian inheritance (Risch & Merikangas, 1993). Mendelian inheritance refers to the situation in which the phenotype is due to the action of a single gene (as in the case of eye color). Complex inheritance refers to the situation in which the combined action of many genes is responsible for the phenotype. All candidate gene studies examine the association between phenotypes and a single gene, as if the genetic risk for eating disorders were transmitted in Mendelian fashion.

Two epidemiological patterns suggest that it is unlikely that a single gene accounts for the genetic risk for eating disorders. First, eating disorders have higher prevalences than typical Mendelian diseases do. Alleles for diseases that are inherited in Mendelian fashion and decrease the ability to survive and have children (as eating disorders do) tend to be removed from the gene pool, resulting in low prevalences. Second, the reported risk ratios for eating disorders in first-degree relatives of eating-disordered probands (that is the likelihood that a person will develop a disease if they have a first-degree relative with the disease versus having no family history of the disease) generally range from 5:1 to 12:1 and fall far below what is expected for a Mendelian disease produced by a dominant gene (5,000:1) or a recessive gene (2,500:1). Risk ratios for Mendelian diseases are decreased when there is reduced penetrance (the genotype does not always lead to the phenotype), variable expressivity (the genotype leads to variable phenotypes), or phenocopies (the phenotype occurs in the absence of the genotype). For example, while a cleft chin is caused by a single, dominant gene, the phenotype associated with this genotype varies, ranging from a clear cleft (Figure 8.6) to smaller depressions. Even with these considerations, however, risk ratios for Mendelian diseases remain well above those reported for eating disorders.

In complex inheritance, each gene contributes a small amount to developing a disorder, and a large number of research participants is needed to show a reliable effect of a specific gene. Thus some inconsistencies in research findings may be caused by inadequate sample sizes as well as not looking at all relevant genes. Given this, an alternative way of examining molecular genetic contributions to eating disorders is to take a completely agnostic approach to what genes may be important by examining all genes. With advances in technology, mapping DNA has become faster and less expensive, introducing the option of genome-wide association studies (GWAS). In a GWAS, researchers evaluate whether or not alleles for

A cleft chin is caused by a single dominant gene, but phenotypic expression of this genotype varies

FIGURE 8.6 A cleft chin is caused by a single dominant gene, but phenotypic expression of this genotype varies.

all genes in the genome are more common in individuals with an eating disorder than in controls. Because looking at so many possible differences creates a high risk of false positive results, the threshold for statistical significance in a GWAS is set at a very stringent level, and these studies require huge samples to detect significant effects.

The first GWAS in AN failed to find a statistically significant difference in allele frequencies between 1,033 AN cases and 3,733 control subjects but did find trend-level associations between polymorphisms for an opioid receptor and for the 5-HT1D receptor (Wang et al., 2011). Similarly, Wade et al. (2013) found no significant associations between particular genes and either disordered eating behaviors or syndromes grouped as “AN spectrum,” “BN spectrum,” and “purging via substances,” but they did find trend- level results for six genes (though none of them related to prior findings in the field). Neither study found the A polymorphism of the 5-HT2A receptor gene to be linked to AN.

A final challenge in the search for genetic loci associated with eating disorders is difficulty defining eating disorder phenotypes. Unlike eye color, where it is reasonably easy to conclude that brown and blue are different colors (and different phenotypes), it remains unclear, for example, whether ANR and ANBP represent one or two disorders. Thus more research on the definition of eating disorders is necessary to identify valid phenotypes. Indeed, this point applies to the full range of studies seeking to understand the pathophysiology of mental disorders and represents the key premise behind the formation of the RDoC initiative, discussed in Chapter 1. Research to better define eating disorders according to core behavioral dimensions rather than complex collections of symptoms will allow more efficient progress toward establishing the genetic and neurobiological underpinnings of eating disorders.

Given the challenges facing molecular genetic research, the findings suggesting an association between the 5-HT2A receptor gene and AN are quite promising. It is also important to acknowledge an advantage that molecular genetic research has in the search for the biological bases of eating disorders. Unlike other potential biological contributors, gene sequences do not alter as a function of the presence or absence of an eating disorder. Thus it is possible to examine candidate genes among individuals with eating disorders without worrying that an association between a specific genotype and the presence of an eating disorder reflects the effect of the disorder on the genome. In the next section we turn to the profound effects that eating disorders can have on the body.

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