Human Molecular Genetics Advance Access originally published online on December 5, 2005
Human Molecular Genetics 2006 15(2):251-258; doi:10.1093/hmg/ddi441
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A genome-wide linkage scan of familial benign recurrent vertigo: linkage to 22q12 with evidence of heterogeneity
1Department of Human Genetics, 2Department of Neurology, 3Department of Statistics, 4Department of Surgery and 5Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
* To whom correspondence should be addressed at: Department of Human Genetics, University of California, 5506A Gonda, 695 Charles E. Young, Los Angeles, CA 90095, USA. Tel: +1 310 794 7981; Fax: +1 310 794 5446; Email: snelson{at}ucla.edu
Received October 18, 2005; Accepted November 25, 2005
Benign recurrent vertigo (BRV) is a common disorder affecting up to 2% of the adult population and may be etiologically related to migraine because of similarities in the clinical spectrum of the phenotypes and a high co-morbidity within families. Many families have multiple-affected genetically related individuals suggesting familial transmission of the disorder with moderate to high penetrance. While clinically similar to episodic ataxias, there are currently no genes identified that contribute to BRV and no systematic linkage studies performed. In an initial effort to genetically define BRV, we have selected from our Neurology Clinic population a subset of 20 multigenerational families with apparent autosomal dominant transmission, and performed genetic linkage mapping using both parametric and non-parametric linkage (NPL) approaches. The Affymetrix 10K SNP Mapping Assay was used for the genotyping. Heterogeneity LOD (HLOD) analysis reveals the evidence of genetic heterogeneity for BRV and evidence of linkage in a subset of the families to 22q12 (HLOD=4.02). An additional region was identified by NPL analysis at 5p15 (LOD=2.63). As migraine is observed substantially more commonly both within the BRV-affected individuals and the related family members, it is possible that a form of migraine is allelic to the BRV locus at 22q12. However, testing linkage or the chromosome 22q12 region to a broader migraine/vertigo phenotype by defining affectation status as either migrainous headaches or BRV greatly weakened the linkage signal, and no significant other peaks were detected. Thus, BRV and migraine does not appear to be allelic disorders within these families. We conclude that BRV is a heterogeneous genetic disorder, appears genetically distinct from migraine with aura and is linked to 22q12. Additional family and population-based linkage and association studies will be needed to determine the causative alleles.
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