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

Weak support for linkage of schizophrenia to proximal Xq has previously bee n reported. In addition, an increased prevalence of thyroid disorder has be en noted in families of individuals with schizophrenia, Recently, a gene ma pped to Xq13 termed HOPA has been found to be associated with mental retard ation, 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, se veral of whom (n = 53) also had a family history of hypothyroidism. Four ma les and two females were found with an alteration in exon 42 of the HOPA ge ne compared with 8/492 males and 18/471 females (942 X chromosomes) compare d 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 varia tion were subsequently screened, the mutation did not segregate with schizo phrenia in three of five families, although all 6 probands with an exon 42 variation did have hypothyroidism in either themselves (n = 3) or their mot hers (n = 3) (P < 0.008). These findings replicate prior findings demonstra ting an association between HOPA polymorphisms and hypothyroidism. In addit ion, the increased frequency of HOPA variants in this population may also p rovide a genetic basis for the familial association of thyroid disease and schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 98:398-403, 2000 . (C) 2000 Wiley-Liss, Inc.