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Genetic refinement and physical mapping of a 2.3 Mb probable disease region associated with a bipolar affective disorder susceptibility locus on chromosome 4q35
Author(s) -
Badenhop Renee F.,
Moses Melissa J.,
Scimone Anna,
Adams Linda J.,
Kwok John B.J.,
Jones AnneMarie,
Davison Gail,
Evans Mary R.,
Kirkby Kenneth C.,
Hewitt Jane E.,
Donald Jennifer A.,
Mitchell Philip B.,
Schofield Peter R.
Publication year - 2002
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.10023
Subject(s) - genetics , locus (genetics) , haplotype , genetic linkage , pedigree chart , contig , biology , allele , identity by descent , genetic marker , chromosomal region , gene mapping , gene , chromosome , genome
A susceptibility locus for bipolar affective disorder has been mapped to chromosome 4q35 in a large multigenerational pedigree. We have expanded this analysis to include 55 pedigrees (674 individuals, 214 affecteds). The evidence for linkage to 4q35 was strengthened in this larger cohort, with a maximum two‐point LOD score of 3.2 for marker D4S1652. Several other markers in the region gave LOD scores greater than 1.5. Non‐parametric analysis provided additional support for linkage to the 4q35 region. To further refine this region, haplotype analysis was carried out in 16 of the 55 pedigrees that showed evidence of linkage. As there is no evidence for an ancestral haplotype, nor a one‐to‐one correspondence between the disease and putative disease haplotype, we undertook an analysis based on pedigree‐specific, identical‐by‐descent allele‐sharing in order to define a probable disease region. This analysis indicated that the percentage sharing of alleles, identical‐by‐descent, in affecteds of all linked pedigrees increases from 60% at the centromeric markers to 75% for markers at the telomere. Maximal allele sharing occurred between markers D4S3051 and 4qTEL13 with this 24 cM region defining a probable disease region. We have constructed a physical map of the 4q35 interval consisting of a YAC contig and BAC clones. Based on this map the probable disease region between D4S3051 and 4qTEL13 corresponds to only 2.3 Mb. This region is very gene poor with only three known genes indicated from the YAC/BAC map. The small number of genes will facilitate systematic screening for variations associated with bipolar disorder. © 2003 Wiley‐Liss, Inc.