Haplotype Analysis and a Novel Allele-Sharing Method Refines a Chromosome 4p Locus Linked to Bipolar Affective Disorder

• Published in: Biological psychiatry (1969) Vol. 61; no. 6; pp. 797 - 805
• Main Authors: Le Hellard, Stephanie, Lee, Andrew J, Underwood, Sarah, Thomson, Pippa A, Morris, Stewart W, Torrance, Helen S, Anderson, Susan M, Adams, Richard R, Navarro, Pau, Christoforou, Andrea, Houlihan, Lorna M, Detera-Wadleigh, Sevilla, Owen, Michael J, Asherson, Philip, Muir, Walter J, Blackwood, Douglas H.R, Wray, Naomi R, Porteous, David J, Evans, Kathryn L
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2007
• Subjects: Allele sharing; Alleles; bipolar affective disorder; Bipolar Disorder - genetics; chromosome 4p; Chromosomes, Human, Pair 4 - genetics; Female; Genetic Linkage; Haplotypes - genetics; Humans; linkage; Lod Score; Male; Models, Genetic; Pedigree; Polymorphism, Single Nucleotide; Population Surveillance; Psychiatry; recurrent unipolar depression; schizophrenia; linkage; schizophrenia; Allele sharing; recurrent unipolar depression; chromosome 4p; bipolar affective disorder
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2006.06.029

Background Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. Methods We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. Results We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. Conclusions Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.