No Evidence for Significant Linkage between Bipolar Affective Disorder and Chromosome 18 Pericentromeric Markers in a Large Series of Multiplex Extended Pedigrees

James A. Knowles,1,2 Peter A. Rao,1 Tara Cox-Matise,3 Jo Ellen Loth,1 Gracielle M. de Jesus,1 Laura Levine,1 Kamna Das,1 Graciela K. Penchaszadeh,1 Joyce R. Alexander,4 Bernard Lerer,4 Jean Endicott,1 Jurg Ott,3 T. Conrad Gilliam,1,2 and Miron Baron1,2
1Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute,
2Columbia Genome Center, and
3Laboratory of Statistical Genetics, Rockefeller University, New York; and
4 Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem

American Journal of Human Genetics , 62, 916-924 (1998)

Abstract

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.