Genomewide linkage scan in schizoaffective disorder: Significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13

Context: Traditionally, the search for genes involved in predisposition to major psychoses has proceeded with separate studies of schizophrenia and bipolar disorder. However, twin data suggest that, in addition to genes with specificity for these phenotypes, there exist genes that simultaneously influence susceptibility to schizophrenia, bipolar disorder, and schizoaffective disorder. Objective: To undertake, to our knowledge, the first systematic search for such loci. Design: Genomewide linkage scan. Setting: Affected individuals were ascertained in the United Kingdom and Ireland from general psychiatric inpatient and outpatient services. Participants: The families were selected for linkage studies of either schizophrenia or bipolar disorder. Pedigrees were selected for the current analysis where there was at least 1 member with DSM-IV schizoaffective disorder, bipolar type. Within these pedigrees, individuals were coded as affected if they had been diagnosed with DSM-IV schizophrenia, schizoaffective disorder of bipolar type, or bipolar I disorder. A total of 24 pedigrees contributed 35 affected sibling pairs to the sample. Method: A 10-centimorgan genome scan using microsatellite markers was analyzed using MAPMAKER/SIBS software. Results: Agenomewide significant signal (LOD=3.54) was observed at chromosome 1q42 (near D1S2800), and suggestive LOD scores were observed at chromosomes 22q11 (LOD=1.96) and 19p13 (LOD=1.85). No linkage was observed in these regions in our original schizophrenia or bipolar scans in individuals from the United Kingdom. Conclusions: Our linkage findings strongly support the existence of loci that influence susceptibility across the functional psychosis spectrum. The DISC1 gene lies within 2.5 megabases of our peak marker on chromosome 1q42 and has been previously implicated in schizophrenia, bipolar disorder, and, recently, schizoaffective disorder. Follow-up of this region should use samples enriched for cases of schizoaffective disorder. Our findings have similar implications for the search for genetic variation on chromosome 22q11 that influences susceptibility to psychosis.