A genome-wide linkage study of bipolar disorder and co-morbid migraine: Replication of migraine linkage on chromosome 4q24, and suggestion of an overlapping susceptibility region for both disorders on chromosome 20p11☆
Abstract
Migraine and Bipolar Disorder (BPAD) are clinically heterogeneous disorders of the brain with a significant, but complex, genetic component. Epidemiological and clinical studies have demonstrated a high degree of co-morbidity between migraine and BPAD. Several genome-wide linkage studies in BPAD and migraine have shown overlapping regions of linkage on chromosomes, and two functionally similar voltage-dependent calcium channels CACNA1A and CACNA1C have been identified in familial hemiplegic migraine and recently implicated in two whole genome BPAD association studies, respectively. We hypothesized that using migraine co-morbidity to look at subsets of BPAD families in a genetic linkage analysis would prove useful in identifying genetic susceptibility regions in both of these disorders. We used BPAD with co-morbid migraine as an alternative phenotype definition in a re-analysis of the NIMH Bipolar Genetics Initiative wave 4 data set. In this analysis we selected only those families in which at least two members were diagnosed with migraine by a doctor according to patients' reports. Nonparametric linkage analysis performed on 31 families segregating both BPAD and migraine identified a linkage signal on chromosome 4q24 for migraine (but not BPAD) with a peak LOD of 2.26. This region has previously been implicated in two independent migraine linkage studies. In addition we identified a locus on chromosome 20p11 with overlapping elevated LOD scores for both migraine (LOD
=1.95) and BPAD (LOD=1.67) phenotypes. This region has previously been implicated in two BPAD linkage studies, and, interestingly, it harbors a known potassium dependant sodium/calcium exchanger gene, SLC24A3, that plays a critical role in neuronal calcium homeostasis. Our findings replicate a previously identified migraine linkage locus on chromosome 4 (not co-segregating with BPAD) in a sample of BPAD families with co-morbid migraine, and suggest a susceptibility locus on chromosome 20, harboring a gene for the migraine/BPAD phenotype. Together these data suggest that some genes may predispose to both bipolar disorder and migraine.
Keywords: Migraine, Bipolar disorder, Linkage, Chromosome 4q24, Chromosome 20p11
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☆ NIMH Genetics Initiative for Bipolar Disorder Consortium authors include: J. Nurnberger, Indiana University; W. Byerley, University of California, San Francisco; J. Kelsoe, University of California, San Diego; M. McInnis, University of Michigan; J. Potash, Johns Hopkins; E. Gershon, University of Chicago; W. Scheftner, Rush University Medical Center; W. Coryell, University of Iowa; W. Berrettini, University of Pennsylvania; F. McMahon, National Institute of Mental Health; J. Rice, Washington University.
PII: S0165-0327(09)00273-0
doi:10.1016/j.jad.2009.06.014
© 2009 Elsevier B.V. All rights reserved.
