Investigation of a candidate gene for schizophrenia on Xq13 previously associated with mental retardation and hypothyroidism

Abstract

Weak support for linkage of schizophrenia to proximal Xq has previously been reported. In addition, an increased prevalence of thyroid disorder has been noted in families of individuals with schizophrenia. Recently, a gene mapped to Xq13 termed HOPA has been found to be associated with mental retardation, hypothyroidism, and depression and to function as a coactivator for the thyroid receptor. We therefore examined the HOPA gene in a group of 111 probands from a larger cohort of multiplex families with schizophrenia, several of whom (n = 53) also had a family history of hypothyroidism. Four males and two females were found with an alteration in exon 42 of the HOPA gene compared with 8/492 males and 18/471 females (942 X chromosomes) compared with consecutively screened newborns (chi(2) = 3.92, P < 0.05). However, when available family members of each of the probands with an exon 42 variation were subsequently screened, the mutation did not segregate with schizophrenia in three of five families, although all 6 probands with an exon 42 variation did have hypothyroidism in either themselves (n = 3) or their mothers (n = 3) (P < 0.008). These findings replicate prior findings demonstrating an association between HOPA polymorphisms and hypothyroidism. In addition, the increased frequency of HOPA variants in this population may also provide a genetic basis for the familial association of thyroid disease and schizophrenia.

A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia

“…In particular, we have been interested in the population history of the HOPA 12bp polymorphism and its risk for psychosis and hypothyroidism. In some, but not all, prior studies this polymorphism has been associated with a low, but significant risk for schizophrenia in individuals of northern European extraction (DeLisi et al, 2000;Philibert et al, 2001;Kirov et al, 2003), whereas another group has shown the allele to be absent in individuals of Chinese descent (Hung et al, 2003). Although the latter is not unexpected as the allele appears to be of recent evolutionary origin (Spinks et al, 2004) and may not have been present when the founders of the common gene pool began to diverge approximately 130-170 000 years ago (Leigh, 2003), the failure of Kirov and colleagues to demonstrate significant main effects in the earlier work is puzzling and could be secondary to poor power if the effect of the HOPA 12bp allele is less than a two-fold risk.…”

“…One other study, by Hung et al (2003), examined Chinese probands. As two of the studies, by DeLisi et al (2000) and by Philibert et al (2001), used a partially overlapping control population consisting of random newborns, the allele counts from the first study were added to the second population with the result that the two studies counted as only one independent study. In contrast, Kirov and colleagues reported association analyses in two separate populations using a variety of comparison populations.…”

Mosaic Turner syndrome associated with schizophrenia

“…Hypothyroidism in our case was caused by Hashimoto thyroiditis. Several studies reveled that schizophrenia is linked with some autoimmune diseases, especially autoimmune thyroid disease, type 1 diabetes, celiac disease, rheumatoid arthritis16,18). She might be the similar case of comorbid TS and schizophrenia, mental retardation, hypothyroidism, which speculated the genetic possibility such as the HOPA gene on the X chromosome might be involved in the development of schizophrenia.…”

Editorial [ Hot Topic: Wnt Signaling (Guest Editor: Rashna D. Balsara) ]

“…One subunit of the mediator complex, MED12, contains a domain (the opa domain) which is responsible for mediating Wnt pathway signaling. In 2000, a 4 amino acid insertional polymorphism in this domain was reported to be linked to schizophrenia [142]. Since that time other variations in the same domain have also shown linkage.…”