A genome-wide linkage analysis of migraine in the descendents of the Bounty Mutineers implicates the 13q chromosomal region

Abstract

Objectives. The aims of the present study were to characterise the demographics and molecular genetics of migraine in a large pedigree derived from a known population isolate, Norfolk Island. We also aimed to determine the heritability, the impact of ancestry on affection status and lastly, perform genome-wide linkage screening to localise regions that may potentially harbor susceptibility genes in this unique population. Background. Norfolk Island is a small volcanic land mass, situated in the South Pacific Ocean approximately 1,500km southeast of Brisbane, Australia. The island was settled in 1856 by Pitcairn Islander's descended from a limited number (<20) of English Bounty mutineer and Tahitian founders. To this day, approximately 80% of the permanent adult residents inhabiting Norfolk possess ancestral lineages to the original population founders. Previous epidemiological and genetic studies of cardiovascular risk traits and linkage disequilibrium suggest that the Norfolk population may be of particular use in investigating complex multifactorial disorders, including migraine. Methods. DNA samples from two-thirds of the permanent adult population have been prepared and phenotypes relating to migraine obtained. Most of these individuals fit within a single large, 12-generational (~6500 individuals) pedigree extending back to the original founders. Heritability and power estimates have been determined and linkage disequilibrium investigated. We have also undertaken a full microsatellite genome scan using this population. Results were analysed using non-parametric variance component linkage methods. Results. Migraine was diagnosed in accordance with International Headache Society guidelines. Using a combined migraine with (MA) and without aura (MO) phenotype, the cohort was observed to have an overall migraine prevalence of 24%, with approximately 33% of women and 12% of men affected. Admixture analysis indicated that Polynesian ancestry had no significant effect on migraine status (p=0.70). Heritability screening of the MA/MO phenotype estimated a genetic liability of 42% (p<0.05). Linkage analysis identified a peak signal on chromosome 13q33.1 (point-wise p-value = 0.006). To further investigate this locus, we chose to stratify this peak finding using trait component analysis. Results revealed suggestive evidence of linkage also to the chromosome 13 for a combined photophobia and/or phonophobia phenotype (LOD=2.11; p=0.0009). Conclusions. Migraine has an elevated prevalence in the descendents of the Bounty Mutineers and heritability estimates support a significant genetic component in this population. Results from a genome wide linkage analysis in this population replicate linkage previously detected on chromosome 13 in a Dutch cohort. Our population isolate results thus support the involvement of 13q in migraine susceptibility.