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Genetic isolates have been useful cohorts in which to search for genes underlying disorders of unknown pathology. One such cohort is thought to exist in the Central Valley of Costa Rica surrounding the city of San Jose. Previous investigators identified a rare dominant gene for hereditary deafness in this population, and a suggestive linkage of severe bipolar psychosis has been reported in another study. Ninety-nine families with at least one pair of siblings affected with schizophrenia or a schizophrenia-spectrum diagnosis had clinical evaluations and DNA collected for genotyping. The Marshfield Medical Research Foundation (NHLBI) Mammalian Genotyping Service performed all genotyping using 404 short-tandem repeat polymorphic markers (STRPs) spaced on average 10 cM apart. Data were analyzed using the nonparametric program, GeneHunterPlus. The population structure was investigated using the STRUCT program. No region was found with genome-wide significance for linkage. Using a phenotype of schizophrenia plus schizoaffective disorder, the highest maximum likelihood score (MLS) observed was 1.78 (P < 0.004) at 176.6 cM from pter on chromosome 5q, an area previously implicated by some other groups. In addition, five regions on chromosomes 1p, 2p, 2q, 14p, and 8p had MLSs above 1.0. All other regions produced scores below 1.0. Population genetic analysis reveals no evidence for population substructure, for admixture with other populations, such as Amerindians, or for inbreeding in the parental generation. The latter casts some doubt on this population being an isolate, although there was evidence of inbreeding among the offspring.

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.

Direction and degree of handedness in humans are variable between individuals and thought to be in part inherited. Several studies have shown an increase in non-right handedness among patients with schizophrenia, and some have included unaffected relatives. The present study was designed to determine whether reduced right handedness is more frequent among individuals with schizophrenia as compared with their well relatives and whether it clusters within families having multiple ill members. A total of 259 families comprising 418 individuals diagnosed with schizophrenia or schizoaffective disorder, 54 individuals with other psychoses, 145 family members with depression and other minor diagnoses, and 288 unaffected individuals were included. Hand preference was assessed by the Annett Scale and right relative to left hand skill measured using the Tapley-Bryden test. For all assessments of hand preference and hand skill, females were significantly more lateralised towards the right than males. Those individuals with schizophrenia or schizoaffective disorder had significantly less right hand preference than their unaffected relatives when measured as a quantitative index of items from the Annett Scale (p = .019), but not categorically (right, left or mixed). In contrast, there was no difference in hand skill between diagnostic groups. Hand preference was significantly correlated among male-male affected sibling pairs (p = .01) and similar results were found for hand skill among the total group of affected pairs (p = .001). Although these results only partially support a relationship between handedness and schizophrenia, they nevertheless draw attention to sex differences in hand preference and the familial aspects of hand preference in this disorder. More direct approaches to the genetics of cerebral dominance and psychosis are required.