The association of a HOPA polymorphism with major depression and phobia

Thyroid hormone has a prominent role in the development and homeostasis of the central nervous system (CNS). Consequently, genes participating in thyroid hormone receptor (THR)-mediated signal transduction are prime candidates for neuropsychiatric illness susceptibility factors. Previously, we have associated exonic polymorphisms in a Xq13 thyroid receptor coactivator named HOPA with a modest increase in vulnerability to a broad spectrum of neuropsychiatric illness, including depression, psychosis, and hypothyroidism. In order to test and extend these findings, we have now examined the relationship between HOPA polymorphisms and neuropsychiatric illness in a cohort of Iowa adoptees. Consistent with our prior findings, HOPA polymorphisms were associated with an increased risk for major depression. There was suggestive evidence that the increased psychiatric morbidity in these subjects could represent epistasis, e.g., an interaction between the HOPA variant and a genetic diathesis for another psychiatric condition such as biologic parent antisocial behavior. Information about biologic parent behavior and the adoptive home environment was used to determine depressive symptoms attributable to gene-environment interaction. HOPA variant subjects continued to show significant differences in depressive symptoms when controlling for gene-environment interaction. Finally, because obesity is associated with hypothyroidism and HOPA polymorphisms are associated with hypothyroidism, we analyzed weight with respect to HOPA allele status. We found that that HOPA polymorphisms were associated with increased risk for obesity ( P < .001). In summary, we conclude that HOPA polymorphisms may be a moderate risk factor for increased susceptibility to a broad spectrum of neuropsychiatric illness and hypothesize that the type of illness manifested might be related to a separate genetic diathesis.