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.

Parental and comorbid migraine in individuals with bipolar disorder: A nationwide register study

“…The results of our study indicate that parental migraine, even in the absence of parental BD, is a risk factor for BD in the offspring. Therefore, our study provides epidemiological support for genetic studies indicating a genetic overlap between BD and migraine (Oedegaard et al, 2010a; Oedegaard et al, 2010b). However, the associations with BD found in our study were stronger for comorbid migraine than for parental migraine.…”

“…However, BD and migraine have pathophysiological similarities in terms of altered neurotransmission of dopamine (Cousins et al, 2009; Peroutka et al, 1997) and serotonin (Hamel, 2007; Mahmood and Silverstone, 2001). Genetic factors contribute greatly to the development of both BD and migraine, and genome-wide linkage and association studies have found overlapping regions between these two disorders (Oedegaard et al, 2010a; Oedegaard et al, 2010b). If the co-occurrence of BD and migraine is predominantly due to a genetic link between these disorders, then a familial clustering of BD and migraine would be expected.…”

Genetic Influences on Response to Novel Objects and Dimensions of Personality in Papio Baboons

“…While each of these results alone is interesting, their mapping to overlapping locations makes these results more compelling. Furthermore, the region of human chromosome 20 (HSA20) that is homologous to the segment of PHA10 containing this baboon QTL has been implicated in conditions such as restless legs syndrome (Levchenko et al 2006), migraine (Oedegaard et al 2010), and bi-polar disorder (Etain et al 2010). While the connection between these conditions and our baboon personality phenotypes may not be immediately obvious, dysregulation of the dopaminergic system is a suspected influence on each human phenotype.…”

Confirmation that Xq27 and Xq28 are susceptibility loci for migraine in independent pedigrees and a case-control cohort

“…The Xq27 region has now been implicated in migraine in three independent studies. Oedegaard and colleagues [18] conducted a genome-wide linkage study of bi-polar disorder and comorbid migraine using pedigrees derived from the National Institute of Mental Health (NIMH) Genetics Initiative for Bipolar Disorder. They identified a linkage peak with a LOD score of 1.6 (P00.003) in the Xq27 region (marker DXS9908 approx 1 Mb from DXS8043) that segregated with only the migraine and not the bipolar phenotype.…”