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Genomewide Linkage Scan in Schizoaffective Disorder
Significant Evidence for Linkage at 1q42 Close to DISC1, and Suggestive Evidence at 22q11 and 19p13
Marian L. Hamshere, PhD;
Phil Bennett, PhD;
Nigel Williams, PhD;
Ricardo Segurado, PhD;
Alastair Cardno, PhD, MRCPsych;
Nadine Norton, PhD;
David Lambert, PhD;
Hywel Williams, PhD;
George Kirov, MD, MRCPsych;
Aiden Corvin, MD, MRCPsych;
Peter Holmans, PhD;
Lisa Jones, PhD;
Ian Jones, PhD, MRCPsych;
Michael Gill, MD, MRCPsych;
Michael C. O’Donovan, PhD, FRCPsych;
Michael J. Owen, PhD, FRCPsych;
Nick Craddock, PhD, FRCPsych
Arch Gen Psychiatry. 2005;62:1081-1088.
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 A genomewide 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.
Author Affiliations: Department of Psychological Medicine (Drs Hamshere, N. Williams, Cardno, Norton, H. Williams, Kirov, I. Jones, O’Donovan, Owen, and Craddock) and Biostatistics and Bioinformatics Unit (Drs Hamshere and Holmans), School of Medicine, Cardiff University, Cardiff, Wales; Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, England (Drs Bennett and L. Jones); and Departments of Psychiatry and Genetics, Trinity College, Dublin, Ireland (Drs Segurado, Lambert, Corvin, and Gill).
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