Evidence for a Schizophrenia Vulnerability Locus on Chromosome 8p in the Irish Study of High-Density Schizophrenia Families

Kendler, Kenneth S. MD
MacLean, Charles J. PhD
O'Neill, F. Anthony MD
Burke, John MB
Murphy, Bernadette MB
Duke, Fiona MB
Shinkwin, Rosemary MB
Easter, Stephen M. MS
Webb, Bradley T. BS
Zhang, Jie MS
Walsh, Dermot MB, FRCPI
Straub, Richard E. PhD

Received Jan. 24, 1996; revision received June 7, 1996; accepted July 1, 1996. From the Departments of Psychiatry and Human Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond; the Department of Psychiatry, School of Medicine, Queen's University, Belfast, U.K.; and the Health Research Board, Dublin. Address reprint requests to Dr. Kendler, Psychiatric Genetics Research Program, Virginia Institute for Psychiatric and Behavioral Genetics, P.O. Box 980126, Richmond, VA 23298-0126.
Largely supported by NIMH grants MH-41953 and MH-45390. Dr. Kendler is supported by Research Scientist Award MH-01277 from NIMH.
The authors thank S. Humphries, M. Healy, and A. Finnerty for supervision of data collection; M. Ni Nuallain, F. McMahon, J. Downing, T. Hebron, B. Hanratty, E. Crowe, M. Doherty, J. Bray, and L. Lowry for additional interviews; the families and hospital staffs for cooperation; and B. Kipps, C. L. Jackson, K. Williams, L. Thacker, B. Duke, R. McClelland, and L. Kruglyak for assistance.

American Journal of Psychiatry 153(12):p 1534-1540, December 1996.

Objective

This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues. Method: The linkage sample of the Irish Study of High-Density Schizophrenia Families consists of 265 multiplex families containing 1,408 individuals. Fifteen markers covering 30 centimorgans on chromosome 8p were tested. Three statistical methods were used: two-point and multipoint heterogeneity lod scores and a multipoint nonparametric test. Results: According to twopoint heterogeneity lod scores, the strongest evidence for linkage was found for markers D8S1731 (maximum lod score=2.00), D8S1715 (maximum lod score=2.52), and D8S133 (maximum lod score=2.08) by assuming a phenotypic definition of all psychiatric illness and a range of genetic models. According to multipoint heterogeneity lod scores, the strongest evidence for linkage (maximum lod score=2.34), found by using a dominant genetic model and a broad definition of the schizophrenia spectrum, extended over a 10-cM region between markers D8S1715 and D8S1739. Multipoint nonparametric linkage found the strongest evidence (maximum z=2.51) over a broader region when either a diagnosis of core schizophrenia or a narrow definition of the schizophrenia spectrum was used. This putative vulnerability locus was segregating in 10%-25% of the families studied. Conclusions: This study supports the existence of a vulnerability locus for schizophrenia on chromosome 8p. In this sample, this locus appears to influence the risk of illness in only a modest proportion of families and predisposes to a range of schizophrenia spectrum and possibly nonspectrum disorders.

(Am J Psychiatry 1996; 153:1534-1540)