Schizophrenia Genetics

Genetic risk and early onset schizophrenia

If there is a continuum of transmitted liability for schizophrenia then, as with other disorders of presumed multifactorial origin, early onset cases of schizophrenia should be associated with a greater genetic loading (Childs & Scriver 1986). Pulver et al. (1990) found an increased morbid risk of schizophrenia in relatives of male probands under the age of 17. Meanwhile, Sham et al. (1994) found an increased morbid risk in females under age 21 compared with males or later onset females.

While both of these studies suggest an inverse relationship between age at onset and transmitted liability, albeit with different gender-specific effects and age cut-offs, it would be dangerous to simply extrapolate these age trends to a younger childhood onset population. Unfortunately, there is a dearth of genetic studies of childhood onset schizophrenia that have used adequate methodology. In the only major twin study of childhood onset schizophrenia, Kallman and Roth (1956) reported an uncorrected MZ concordance rate of 88.2% and a DZ concordance rate of 22.9%. Adult onset schizophrenia clustered in the families of childhood onset probands, providing support for a similar genetic aetiology. Data from family studies suggest that child and adolescent onset schizophrenia carries a greater familial risk of psychosis than adult onset schizophrenia.

In the Maudsley study, Hollis (1999) found that 20% of child and adolescent onset schizophrenia cases had at least one first-degree relative with schizophrenia, and 50% had a first-degree relative with psychosis. These rates are somewhat higher than those reported by Sham et al. (1994) for adult schizophrenic probands (13% of adult probands had a first-degree relative with schizophrenia and 23% had a first-degree relative with any psychosis). Data from the Maudsley study (Hollis 1999) also show that the presence of negative symptoms in the proband predicts a family history of schizophrenia. This provides further support for the idea that negative symptoms may represent the genetically transmitted phenotype in schizophrenia (Tsuang 1993).

Cytogenetic abnormalities

The association between schizophrenia and chromosomal deletions offers another possible clue to the location of candidate genes. The velocardiofacial syndrome (VCFS) microdeletion on chromosome 22q11 is associated with learning difficulties, short stature, palate abnormalities, cardiac anomalies and parkinsonism. VCFS has also been associated with schizophrenia, occurring at a rate of 2% compared with 0.02% in the normal population (Karayiorgou et al. 1995). VCFS appears to be associated with an earlier age of onset of schizophrenia in adults (Bassett et al. 1999). In the NIMH study of childhood onset schizophrenia, five cases out of 47 (10.6%) had previously undetected cytogenetic abnormalities (Nicholson et al. 1999). These included 3/47 (6.3%) with VCFS, one with Turner syndrome (deletion of a long arm of one X chromosome) and one with a balanced translocation of chromosomes 1 and 7. One study has reported an association, found only in males, between childhood onset schizophrenia and an excess of CAG/CTG trinucleotide expansions (Burgess et al. 1998). These findings point to possibly greater genetic heterogeneity in child and adolescent onset forms of schizophrenia.