An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12

Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci. An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1×10−5) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92×10−4), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65×10−4). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women’s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63×10−5) is located within the 5′UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island

Migraine is a common neurovascular disorder with a complex envirogenomic aetiology. In an effort to identify migraine susceptibility genes, we conducted a study of the isolated population of Norfolk Island, Australia. A large portion of the permanent inhabitants of Norfolk Island are descended from 18th Century English sailors involved in the infamous mutiny on the Bounty and their Polynesian consorts. In total, 600 subjects were recruited including a large pedigree of 377 individuals with lineage to the founders. All individuals were phenotyped for migraine using International Classification of Headache Disorders-II criterion. All subjects were genotyped for a genome-wide panel of microsatellite markers. Genotype and phenotype data for the pedigree were analysed using heritability and linkage methods implemented in the programme SOLAR. Follow-up association analysis was performed using the CLUMP programme. A total of 154 migraine cases (25%) were identified indicating the Norfolk Island population is high-risk for migraine. Heritability estimation of the 377-member pedigree indicated a significant genetic component for migraine (h2 = 0.53, P = 0.016). Linkage analysis showed peaks on chromosome 13q33.1 (P = 0.003) and chromosome 9q22.32 (P = 0.008). Association analysis of the key microsatellites in the remaining 223 unrelated Norfolk Island individuals showed evidence of association, which strengthen support for the linkage findings (P ≤ 0.05). In conclusion, a genome-wide linkage analysis and follow-up association analysis of migraine in the genetic isolate of Norfolk Island provided evidence for migraine susceptibility loci on chromosomes 9q22.22 and 13q33.1.

Timing, origin and emplacement dynamics of mass flows offshore of SE Montserrat in the last 110 ka : implications for landslide and tsunami hazards, eruption history, and volcanic island evolution

Mass flows on volcanic islands generated by volcanic lava dome collapse and by larger-volume flank collapse can be highly dangerous locally and may generate tsunamis that threaten a wider area. It is therefore important to understand their frequency, emplacement dynamics, and relationship to volcanic eruption cycles. The best record of mass flow on volcanic islands may be found offshore, where most material is deposited and where intervening hemipelagic sediment aids dating. Here we analyze what is arguably the most comprehensive sediment core data set collected offshore from a volcanic island. The cores are located southeast of Montserrat, on which the Soufriere Hills volcano has been erupting since 1995. The cores provide a record of mass flow events during the last 110 thousand years. Older mass flow deposits differ significantly from those generated by the repeated lava dome collapses observed since 1995. The oldest mass flow deposit originated through collapse of the basaltic South Soufriere Hills at 103-110 ka, some 20-30 ka after eruptions formed this volcanic center. A ∼1.8 km3 blocky debris avalanche deposit that extends from a chute in the island shelf records a particularly deep-seated failure. It likely formed from a collapse of almost equal amounts of volcanic edifice and coeval carbonate shelf, emplacing a mixed bioclastic-andesitic turbidite in a complex series of stages. This study illustrates how volcanic island growth and collapse involved extensive, large-volume submarine mass flows with highly variable composition. Runout turbidites indicate that mass flows are emplaced either in multiple stages or as single events.

Distribution of conjunctival ultraviolet autoflourescence in a population-based study : the Norfolk Island Eye Study

OBJECTIVE: The objective of this study was to describe the distribution of conjunctival ultraviolet autofluorescence (UVAF) in an adult population. METHODS: We conducted a cross-sectional, population-based study in the genetic isolate of Norfolk Island, South Pacific Ocean. In all, 641 people, aged 15 to 89 years, were recruited. UVAF and standard (control) photographs were taken of the nasal and temporal interpalpebral regions bilaterally. Differences between the groups for non-normally distributed continuous variables were assessed using the Wilcoxon-Mann-Whitney ranksum test. Trends across categories were assessed using Cuzick's non-parametric test for trend or Kendall's rank correlation τ. RESULTS: Conjunctival UVAF is a non-parametric trait with a positively skewed distribution. Median amount of conjunctival UVAF per person (sum of four measurements; right nasal/temporal and left nasal/temporal) was 28.2 mm(2) (interquartile range 14.5-48.2). There was an inverse, linear relationship between UVAF and advancing age (P<0.001). Males had a higher sum of UVAF compared with females (34.4 mm(2) vs 23.2 mm(2), P<0.0001). There were no statistically significant differences in area of UVAF between right and left eyes or between nasal and temporal regions. CONCLUSION: We have provided the first quantifiable estimates of conjunctival UVAF in an adult population. Further data are required to provide information about the natural history of UVAF and to characterise other potential disease associations with UVAF. UVR protective strategies should be emphasised at an early age to prevent the long-term adverse effects on health associated with excess UVR.

Prevalence and predictors of refractive error in a genetically isolated population : the Norfolk Island Eye Study

BACKGROUND: We aimed to determine the prevalence and associations of refractive error on Norfolk Island. DESIGN: Population-based study on Norfolk Island, South Pacific. PARTICIPANTS: All permanent residents on Norfolk Island aged ≥ 15 years were invited to participate. METHODS: Patients underwent non-cycloplegic autorefraction, slit-lamp biomicroscope examination and biometry assessment. Only phakic eyes were analysed. MAIN OUTCOME MEASURES: Prevalence and multivariate associations of refractive error and myopia. RESULTS: There were 677 people (645 right phakic eyes, 648 left phakic eyes) aged ≥ 15 years were included in this study. Mean age of participants was 51.1 (standard deviation 15.7; range 15-81). Three hundred and seventy-six people (55.5%) were female. Adjusted to the 2006 Norfolk Island population, prevalence estimates of refractive error were as follows: myopia (mean spherical equivalent ≥ -1.0 D) 10.1%, hypermetropia (mean spherical equivalent ≥ 1.0 D) 36.6%, and astigmatism 17.7%. Significant independent predictors of myopia in the multivariate model were lower age (P < 0.001), longer axial length (P < 0.001), shallower anterior chamber depth (P = 0.031) and increased corneal curvature (P < 0.001). Significant independent predictors of refractive error were increasing age (P < 0.001), male gender (P = 0.009), Pitcairn ancestry (P = 0.041), cataract (P < 0.001), longer axial length (P < 0.001) and decreased corneal curvature (P < 0.001). CONCLUSIONS: The prevalence of myopia on Norfolk Island is lower than on mainland Australia, and the Norfolk Island population demonstrates ethnic differences in the prevalence estimates. Given the significant associations between refractive error and several ocular biometry characteristics, Norfolk Island may be a useful population in which to find the genetic basis of refractive error.

The Norfolk Island Eye Study (NIES) : rationale, methodology and distribution of ocular biometry (Biometry of the Bounty)

Aim: To describe the recruitment, ophthalmic examination methods and distribution of ocular biometry of participants in the Norfolk Island Eye Study, who were individuals descended from the English Bounty mutineers and their Polynesian wives. Methods: All 1,275 permanent residents of Norfolk Island aged over 15 years were invited to participate, including 602 individuals involved in a 2001 cardiovascular disease study. Participants completed a detailed questionnaire and underwent a comprehensive eye assessment including stereo disc and retinal photography, ocular coherence topography and conjunctival autofluorescence assessment. Additionally, blood or saliva was taken for DNA testing. Results: 781 participants aged over 15 years were seen (54% female), comprising 61% of the permanent Island population. 343 people (43.9%) could trace their family history to the Pitcairn Islanders (Norfolk Island Pitcairn Pedigree). Mean anterior chamber depth was 3.32mm, mean axial length (AL) was 23.5mm, and mean central corneal thickness was 546 microns. There were no statistically significant differences in these characteristics between persons with and without Pitcairn Island ancestry. Mean intra-ocular pressure was lower in people with Pitcairn Island ancestry: 15.89mmHg compared to those without Pitcairn Island ancestry 16.49mmHg (P = .007). The mean keratometry value was lower in people with Pitcairn Island ancestry (43.22 vs. 43.52, P = .007). The corneas were flatter in people of Pitcairn ancestry but there was no corresponding difference in AL or refraction. Conclusion: Our study population is highly representative of the permanent population of Norfolk Island. Ocular biometry was similar to that of other white populations. Heritability estimates, linkage analysis and genome-wide studies will further elucidate the genetic determinants of chronic ocular diseases in this genetic isolate.

European and Polynesian admixture in the Norfolk Island population

The Norfolk Island population in the South Pacific is primarily the product of recent admixture between a small number of British male and Polynesian female founders. We identified and genotyped 128 Ancestry Informative Markers (AIMs) spread across the autosomes, X/Y chromosomes and mitochondrial DNA genome, to explore and quantify the current levels of genetic admixture in the Norfolk Islanders. On the basis of autosomal AIMs, the population shows mean European and Polynesian ancestry proportions of 88 and 12%, respectively. However, there is a substantial variation between individuals ranging from total European ancestry to near total Polynesian origin. There is a strong correlation between individual genetic estimates of Polynesian ancestry and those derived from the extensive pedigree and genealogical records of Islanders. Also in line with historical accounts, there is a substantial asymmetry in the maternal and paternal origins of the Islanders with almost all Y-chromosomes of European origin whereas at least 25% of mtDNAs appear to have a Polynesian origin. Accurate knowledge of ancestry will be important in future attempts to use the Island population in admixture mapping approaches to find the genes that underlie differences in the risk to some diseases between Europeans and Polynesians.

Legacy of mutiny on the Bounty : founder effect and admixture on Norfolk Island

The population of Norfolk Island, located off the eastern coast of Australia, possesses an unusual and fascinating history. Most present-day islanders are related to a small number of the 'Bounty' mutineer founders. These founders consisted of Caucasian males and Polynesian females and led to an admixed present-day population. By examining a single large pedigree of 5742 individuals, spanning >200 years, we analyzed the influence of admixture and founder effect on various cardiovascular disease (CVD)-related traits. On account of the relative isolation of the population, on average one-third of the genomes of present-day islanders (single large pedigree individuals) is derived from 17 initial founders. The proportion of Polynesian ancestry in the present-day individuals was found to significantly influence total triglycerides, body mass index, systolic blood pressure and diastolic blood pressure. For various cholesterol traits, the influence of ancestry was less marked but overall the direction of effect for all CVD-related traits was consistent with Polynesian ancestry conferring greater CVD risk. Marker-derived homozygosity was computed and agreed with measures of inbreeding derived from pedigree information. Founder effect (inbreeding and marker-derived homozygosity) significantly influenced height. In conclusion, both founder effect and extreme admixture have substantially influenced the genetic architecture of a variety of CVD-related traits in this population.

Linkage mapping of CVD risk traits in the isolated Norfolk Island population

To understand the underlying genetic architecture of cardiovascular disease (CVD) risk traits, we undertook a genome-wide linkage scan to identify CVD quantitative trait loci (QTLs) in 377 individuals from the Norfolk Island population. The central aim of this research focused on the utilization of a genetically and geographically isolated population of individuals from Norfolk Island for the purposes of variance component linkage analysis to identify QTLs involved in CVD risk traits. Substantial evidence supports the involvement of traits such as systolic and diastolic blood pressures, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, body mass index and triglycerides as important risk factors for CVD pathogenesis. In addition to the environmental inXuences of poor diet, reduced physical activity, increasing age, cigarette smoking and alcohol consumption, many studies have illustrated a strong involvement of genetic components in the CVD phenotype through family and twin studies. We undertook a genome scan using 400 markers spaced approximately 10 cM in 600 individuals from Norfolk Island. Genotype data was analyzed using the variance components methods of SOLAR. Our results gave a peak LOD score of 2.01 localizing to chromosome 1p36 for systolic blood pressure and replicated previously implicated loci for other CVD relevant QTLs.

Phenotypical characterisation of the isolated Norfolk Island population focusing on epidemiological indicators of cardiovascular disease

Objectives Only 193 people from Pitcairn Island, all descended from 9 ‘Bounty’ mutineers and 12 Tahitian women, moved to the uninhabited Norfolk Island in 1856. Our objective was to assess the population of Norfolk Island, several thousand km off the eastern coast of Australia, as a genetic isolate of potential use for cardiovascular disease (CVD) gene mapping. Methods A total of 602 participants, approximately two thirds of the island’s present adult population, were characterized for a panel of CVD risk factors. Statistical power and heritability were calculated. Results Norfolk Islander’s possess an increased prevalence of hypertension, obesity and multiple CVD risk factors when compared to outbred Caucasian populations. 64% of the study participants were descendents of the island’s original founder population. Triglycerides, cholesterol, and blood pressures all had heritabilities above 0.2. Conclusions The Norfolk land population is a potentially useful genetic isolate for gene mapping studies aimed at identifying CVD risk factor quantitative trait loci (QTL).

Association of oestrogen-receptor gene (ESR1) polymorphisms with migraine in the large Norfolk Island pedigree

BACKGROUND: Oestrogen receptor 1 ( ESR1) is located in region 6q25.1 and encodes a ligand-activated transcription factor composed of several domains important for hormone binding and transcription activation. Progesterone receptor ( PGR) is located in 11q22-23 and mediates the role of progesterone interacting with different transcriptional co-regulators. ESR1 and PGR have previously been implicated in migraine susceptibility. Here, we report the results of an association study of these genes in a migraine pedigree from the genetic isolate of Norfolk Island, a population descended from a small number of Isle of Man "Bounty Mutineer" and Tahitian founders.

Prevalence of chronic ocular diseases in a genetic isolate : the Norfolk Island Eye Study (NIES)

Purpose: Over 40% of the permanent population of Norfolk Island possesses a unique genetic admixture dating to Pitcairn Island in the late 18 th century, with descendents having varying degrees of combined Polynesian and European ancestry. We conducted a population-based study to determine the prevalence and causes of blindness and low vision on Norfolk Island. Methods: All permanent residents of Norfolk Island aged ≥ 15 years were invited to participate. Participants completed a structured questionnaire/interview and underwent a comprehensive ophthalmic examination including slit-lamp biomicroscopy. Results: We recruited 781 people aged ≥ 15, equal to 62% of the permanent population, 44% of whom could trace their ancestry to Pitcairn Island. No one was bilaterally blind. Prevalence of unilateral blindness (visual acuity [VA] < 6/60) in those aged ≥ 40 was 1.5%. Blindness was more common in females (P=0.049) and less common in people with Pitcairn Island ancestry (P<0.001). The most common causes of unilateral blindness were age-related macular degeneration (AMD), amblyopia, and glaucoma. Five people had low vision (Best-Corrected VA < 6/18 in better eye), with 4 (80%) due to AMD. People with Pitcairn Island ancestry had a lower prevalence of AMD (P<0.001) but a similar prevalence of glaucoma to those without Pitcairn Island ancestry. Conclusions: The prevalence of blindness and visual impairment in this isolated Australian territory is low, especially amongst those with Pitcairn Island ancestry. AMD was the most common cause of unilateral blindness and low vision. The distribution of chronic ocular diseases on Norfolk Island is similar to mainland Australian estimates.

Shadows : Re-visualising the shark. Developing a framework for hybrid photography in the illumination of nonhuman animal and ecological perspectives at Heron Island and Gladstone, Great Barrier Reef

This study investigated how and to what degree “hybrid photography”—the simultaneous use of indexical and fictional properties and strategies— innovates the representation of animals within animalcentric, ecocentric frameworks. Design theory structured this project’s Practice-led, Visual research methodology framework. Grounded theory processes articulated emerging categories of hybrid photography through systematically and comparatively treating animal photography works for reflexive analysis. Design theory then applied and clarified categories, developing practice that re-visualised shark perspectives as new ecological discourse. Shadows, a creative practice installation, realised a full-scale photographic investigation into shark and marine animal realities of a specific environment—Heron Island and Gladstone, Great Barrier Reef—facing ecological crisis from dredging and development at Gladstone Harbour. Works rendered and explored hybrid photography’s capacity for illuminating nonhuman animals, in particular, sharks, and comprise 65% of this project’s weighting. This exegetical paper offers a definition, strategies and evaluation of hybrid photography in unsettling animal perspectives as effective ecological discourse, and comprises 35%.

Bi-2223 precursor billets for pit wire production

High temperature superconductor precursor billets (feed rods) have been developed for loading into silver tubes. The billets are loaded prior to rolling or drawing operations in PIT wire manufacture. Investigations have shown that wires and tapes prepared from feed rod loaded tubes show enhanced uniformity of electrical transport properties when compared with conventional powder packing, especially in wires drawn to long lengths. Analysis on production feed rods have shown carbon content to be as low as 110 ppm. © 1999 IEEE.

Weak key-IV pairs in the A5/1 stream cipher

A5/1 is a shift register based stream cipher which provides privacy for the GSM system. In this paper, we analyse the loading of the secret key and IV during the initialisation process of A5/1. We demonstrate the existence of weak key-IV pairs in the A5/1 cipher due to this loading process; these weak key-IV pairs may generate one, two or three registers containing all-zero values, which may lead in turn to weak keystream sequences. In the case where two or three registers contain only zeros, we describe a distinguisher which leads to a complete decryption of the affected messages.