Human Molecular Genetics Advance Access originally published online on August 5, 2003
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Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R167-R172
DOI: 10.1093/hmg/ddg257
© 2003 Oxford University Press
The Newfoundland population: a unique resource for genetic investigation of complex diseases
1Department of Medicine, 2Department of Genetics, 3Department of History and 4Department of Pediatrics, Memorial University of Newfoundland, St Johns, Newfoundland, Canada, 5Newfound Genomics and Center for Neurobehavioral Genetics, St Johns, Newfoundland, Canada and 6Departments of Psychiatry and Human Genetics, UCLA, Los Angeles, CA, USA
Received June 23, 2003; Accepted July 29, 2003
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ABSTRACT |
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The population of the province of Newfoundland and Labrador is genetically isolated. This isolation is evidenced by an overabundance of several monogenic disorders. The Newfoundland population, like that of other isolates, is now the focus of interest for identification of genes implicated in common diseases. However, the utility of such populations for this purpose remains unproven. In this paper, we review the current genetic architecture of the province, with respect to geographic isolation, homogeneity, founder effect, genetic drift and extended linkage disequilibrium. Based on these factors, we propose that the population of Newfoundland offers many advantages for genetic mapping of common diseases, compared with admixed populations, and even compared with other isolates.
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INTRODUCTION |
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The population of the province of Newfoundland and Labrador, consisting of the island of Newfoundland and Labrador on the Canadian mainland, is genetically isolated. This isolation is evidenced by an overabundance of several monogenic disorders. For example, there are 27 entries in Online Mendelian Inheritance of Man (www3.ncbi.nlm.nih.gov/omim/) whose genetic basis was significantly elucidated using Newfoundland families. This number of entries is 10-fold higher than that of the neighboring three provinces (Nova Scotia, New Brunswick and Prince Edward Island), when adjusted for population size. Like other genetic isolates that have arisen from a limited founder population, Newfoundland represents an exceptional resource for identifying disease related genes for monogenic disorders.
The Newfoundland population, like that of other isolates, is now the focus of interest for identification of genes implicated in common diseases. However, the utility of such populations for this purpose remains unproven. In this paper, we review the current genetic architecture of the province, with respect to geographic isolation, homogeneity, founder effect, genetic drift and extended linkage disequilibrium (LD).
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HISTORY OF THE NEWFOUNDLAND POPULATION |
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John Cabot first reached Newfoundland in 1497 and seasonal colonies were first established around 1610. The peak immigration to Newfoundland occurred in the mid-1700s, and included mainly Protestant settlers from the south-west of England and Roman Catholic settlers from the south of Ireland (1). Starting from about 20 000 settlers in 1760, the population grew by natural expansion to
200 000 in 1890 (Newfoundland Studies Archives). The present population of the province of Newfoundland and Labrador is 512 930, with 98% of English or Irish descent (Statistics Canada, 2001 and Newfoundland Study Archives). Sixty percent of the current population of Newfoundland reside in communities with 2500 inhabitants or less (Fig. 1; Statistics Canada, 2001). This fact is important for genetic studies, as the average kinship between subpopulations generally decreases with the distance between them; geographic distance is a major determinant of genetic isolation. This rate of expansion is similar to that of other recently founded isolates that have been the focus of genetic mapping studies (2,3).
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PERSISTENT GEOGRAPHIC ISOLATION AND HOMOGENEITY |
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 TOPABSTRACTINTRODUCTIONHISTORY OF THE NEWFOUNDLAND... PERSISTENT GEOGRAPHIC ISOLATION... FOUNDER EFFECTGENETIC DRIFTSIGNAL-TO-NOISE RATIOEXTENDED LINKAGE DISEQUILIBRIUMSUMMARY AND PERSPECTIVESREFERENCES |
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The genetic isolation of three representative outports, two in Newfoundland (one from the east coast and the other from the west coast) and one in Labrador was evaluated formally in 1987 (4). In the eastern Newfoundland outport, only 7–9% of parents came from outside the study area, as did only 0.03% for the west coast outport. Thus, the overwhelming majority of the parents originated from within the study areas. In comparison with present European isolates, the Newfoundland in-migration rates were low and resembled religious isolates such as the Hutterites (5) and Amish (6).
The same east and west outports were used to demonstrate persistent homogeneity of the Newfoundland population (7). The homogeneity coefficient of every individual born in these outports was calculated from reconstructed pedigree data. The average coefficient for individuals born between 1960 and 1979 was 0.0032 and 0.0171 from the east and west outports respectively. These averages are consistent with genetic isolation and are similar to those averages seen in the Hutterites and Amish (5).
Since the above demographic studies, significant out-migration has occurred in selected Newfoundland outports (in the order of 10%). Modernization of some outport communities has also proceeded during this time period. A more recent study examined the outport population using allele frequencies derived from 12 red cell antigens from 10 outports and compared it with parental populations from Ireland and England (8). The authors confirmed persistent genetic isolation in selected outports, but also identified some heterogeneity in the overall population. This study highlights the principle that identifying homogeneous sub-populations in Newfoundland requires consideration of historical events, religion and geography.
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FOUNDER EFFECT |
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A founder effect has been observed in Newfoundland for many Mendelian disorders, including multiple endocrine neoplasia type 1 (9), hereditary non-polyposis colorectal cancer syndrome (HNPCC) (10), hemophilia A (11), and Bardet–Biedl syndrome (12). A single MSH2 mutation has been reported in 50% of Newfoundland families with HNPCC. In contrast, this mutation, on the same haplotype, was observed in only 8% of English HNPCC families (10). This observation is consistent with the hypothesized descent of the Newfoundland population from English founders, and also provides strong evidence for founder effects within this population.
The caspase recruitment domain gene (CARD15) has been identified as a susceptibility gene associated with Crohn's disease (13) and more recently with psoriatic arthritis (14). We investigated this gene, looking for a founder effect in Newfoundland for a susceptibility allele for these diseases. The Arg702Trp variant accounts for 71% of Newfoundland CARD15 Crohn's mutations, compared with 35% of European CARD15 mutations and 40% of Quebec CARD15 mutations (15,16). Interestingly, the Arg702Trp variant also accounts for 70% of the CARD15 mutations for psoriatic arthritis in Newfoundland (14).
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GENETIC DRIFT |
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The change in allele frequencies associated with founder effects is called random genetic drift. Because of drift, founder populations often have an elevated incidence of particular genetic disorders. Indeed this is the case in Newfoundland for rare monogenic disorders such as Bardet–Biedl syndrome, which has a prevalence of 1 : 17 500 in Newfoundland, compared with 1 : 160 000 in more admixed Caucasian populations of northern European ancestry (17).
Increased incidence of some complex diseases have now also been noted in Newfoundland. We recently determined the annual incidence of juvenile type 1 diabetes mellitus (IDDM), by systematically recording all incident cases of type 1 juvenile diabetes in children less than 1 year of age, over a 5 year period. The average annual incidence rates of juvenile type 1 diabetes in Newfoundland of 40 per 100 000 per year represents the highest known incidence of juvenile IDDM, exceeding that of Sardinia (36.8/100 000) and Finland 36.5/100 000 and far greater than the incidence reported for admixed populations in the US (7–15/100 000) (18). Similar trends have been noted in psoriasis, where the prevalence of disease is 5- to 10-fold higher in Newfoundland than in most other Caucasian populations (19).
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SIGNAL-TO-NOISE RATIO |
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In association studies of common diseases, the etiologic heterogeneity that characterizes such diseases diminishes the probability of detecting a significant signal. In samples from outbred populations, a modest genetic signal may be overlooked unless one assembles very large cohorts of patients. Isolated populations with relative genetic and environmental homogeneity may offer the opportunity for detecting such modest signals. An example, in Newfoundland, is the finding that CARD15 is a susceptibility gene for psoriatic arthritis (14).
A recent study in psoriasis of 499 Caucasian subjects from an admixed North American population failed to find an association between NOD2 (the previous designation for CARD15) and psoriasis (20). A similar lack of association was also noted in an Italian cohort (21). However, a significant association between CARD15 and psoriatic arthritis has been noted in the Newfoundland population [OR 2.97; 95% CI (1.61–5.47); P=0.0005] (14). This study clearly suggests that there is an amplified signal-to-noise ratio, allowing detection of novel associations with a relatively small number of patients from a homogenous population.
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EXTENDED LINKAGE DISEQUILIBRIUM |
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LD refers to the non-random association of alleles at different loci. Probably the most important determinant of LD is the genetic distance between the loci, as very tight linkage results in LD. LD around a disease gene may arise when a limited number of individuals bring a disease mutation into a small population. If the population grows through natural expansion (in the absence of significant in-migration), a high proportion of patients will carry the chromosomal segment on which the disease mutation is sited (22). With each successive generation, recombination ensures that progressively smaller fragments of the founder chromosome remain intact. For many monogenic disorders, disease alleles reveal LD with markers over substantial genetic intervals. For example, in the search, in the Newfoundland population, for a locus for Bardet–Biedl syndrome, a common haplotype of 13 cM on chromosome 2q31 was used to delineate a critical region (12). Analysis of LD has facilitated fine mapping of this locus in this population. With the availability of a dense genome-wide map of single-nucleotide polymorphisms (SNPs), there is now considerable interest in determining whether it is now possible to use LD to perform genome-wide association studies of complex traits in founder populations (23).
To characterize the genome-wide distribution of LD in Newfoundland, we genotyped 200 consecutive unrelated individuals presenting to a blood collection service in St John's. We recruited subjects from St John's because this cosmopolitan city represents the ‘worst case’ scenario in demonstrating extended LD in Newfoundland.
All subjects were genotyped using the Affymetrix HuSNP protocol according to the manufacturer's instructions (24). The HuSNP contains over 1300 individual SNP sites. Our experience was similar to that of previous reports in that more than 200 of these sites on the chip consistently failed, yielding most of the no-signal calls (24). Thus of the 1300 SNPs available in the HuSNP Affymetrix chip, 1064 markers were analyzed. All markers satisfied Hardy–Weinberg equilibrium. All physical positions of the SNPs were derived from the UCSC April 2001 genome assembly.
We estimated the LD between two SNPs using the standardized multiallellic disequilibrium coefficient D' (25). D' is a useful measure of allelic association because it has a simple interpretation, its scale is independent of allele frequency and it is applicable to both SNP and microsatellite data (26). D' varies between 0 (no disequilibrium) and 1 (maximum disequilibrium). D' values for every pair of markers on the same chromosome were determined. This was done by estimating haplotype frequencies for the 200 subjects using the EH program (27). The marker pairs were sorted by physical distance and the moving averages of D' using windows of 10 and 30 markers were calculated. The proportion of pairs with D' >0.33 were estimated because this D' value is commonly regarded as the minimum usable amount of LD (28).
Over 23 000 marker pairs were generated for evaluation. Because the precision and variance of the individual D' estimates suffer at low allele frequencies, we analyzed only SNPs that had a minor allele frequency greater than 10%. LD in Newfoundland exhibited many of the expected features. For the entire data set, LD correlated negatively with distance; however, it was not a monotonic function and varied widely depending on the chromosomal region. We then limited our analyses to the 591 marker pairs separated by <1 Mb, because the expectation would be that a substantial portion of these markers could be in LD.
When all pairs that were separated by <1 Mb were analyzed, at least 50% of all marker pairs exhibited a D'>0.33 at distances of >500 kb. Our finding of an extended linkage disequilibrium in the young founder population of Newfoundland is consistent with what has been seen in other young isolates (23,29,30).
These results contrast with the expectations suggested by widely cited simulation studies (31). Kruglyak (31) has proposed that the extent of LD in isolated populations will not differ from more admixed populations (i.e. expected LD of <3 kb), except if the founding bottleneck was very narrow (10–100 unrelated individuals) or if the frequency of the variant were low (<5%). Kruglyak's contention has been partly supported by empiric studies which reported LD from isolated populations in Finland and Sardina that was similar to LD in admixed populations from the UK and USA (32). However several authors contend that a fair degree of heterogeneity exists within these ‘isolated’ populations, as a result of influences from the many coastal areas and the age of the population (33,34). Another difference between the Newfoundland and the Finish and Sardinian population is the age of the founder population. Finland and Sardinia are considered recent genetic founders (<200 generations), while Newfoundland and Costa Rica are much younger founder populations (35). Indeed, within Finland, recently founded sub-isolates show considerably more extensive LD than the Finnish population as a whole (29).
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SUMMARY AND PERSPECTIVES |
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Over the past 20 years, the province of Newfoundland has been the subject of intensive genetic and molecular research. Most discoveries which have been made are related to rare monogenic disorders. This partly reflected the limited technological ability of the field to identify susceptibility genes of modest effect. Rapid advances in high-throughput genotyping, coupled with the availability of a plethora of markers and state of the art bio-informatics and statistical genetics, offer the opportunity to now identify such genes.
Numerous genetic studies presently focus on founder populations (36,37). The benefit of such founder populations over heterogeneous populations to identify genes for rare monogenic disorders is unquestioned. It has been suggested that a founder population exhibiting extended linkage disequilibrium and a greater kinship coefficient would have increased power to identify genes in complex disease. Others have argued against any perceived or real benefit from using a founder population for identifying genes in complex disorders. Thus the utility of a founder population for identification of genes in complex disease is now being debated. In this manuscript, we demonstrate that the province of Newfoundland offers many advantages in gene mapping as a result of its population and genetic architecture for the following reasons.
Newfoundland is a very young founder population (<20 generations) with a limited number of founders, as compared with many present-day European isolates with multiple founders encompassing many more generations. Other very young founder populations include the Central Valley of Costa Rica (38), the Afrikaners of South Africa (30) and the Hutterites (39). These young founder populations have demonstrated longer stretches of LD than in typically older European isolates (36). For instance, when the background level of LD in the Afrikaner population was evaluated, this genetic isolate reported extending remarkably over a 6 cM range.
Genetic isolation and homogeneity persist in selected Newfoundland outports. Although the studies by Bear were published in the late 1980s, little immigration has occurred in many of these communities (4,7). Thus the homogeneity of these communities is unlikely to have been diluted as a result of recent admixture. However with improvements in transportation and significant out-migration from the Newfoundland outports, fewer of the communities can be considered true genetic isolates than in the past. Along with the geographic isolation, the Newfoundland population demonstrates a high degree of cultural and environmental homogeneity, which also probably adds to the signal-to-noise ratio for genetic mapping. Because there is likely to be substantial mutational complexity for common susceptibility genes, the presence of limited variability of disease causing alterations in Newfoundland will result in a substantial mapping advantage. The increased allelic homogeneity will also facilitate the efficiency of LD mapping in this population.
Many chromosomal regions of extended LD have been noted in identifying genes which cause rare monogenic disorders. However the disequilibrium that results from Mendelian disorders offers little insight for complex diseases, because these mutations are likely relatively rare and may very well be recent. Disequilibrium patterns for marker polymorphisms, as analyzed in our study, may be more reflective of complex disease alleles because they are relatively high in frequency and tend to persist in populations for long periods of time. We noted extended LD in the Newfoundland population. This result should be interpreted with some caution until our findings are extended in larger samples and with more markers. Our results are consistent with the results seen in other very young founder populations from the Central Valley of Costa Rica, Palau, and in Afrikaners of South Africa, where LD was detected over long distances (30,38,40).
If the extensive LD that we observed in Newfoundland occurs throughout the genome, a relatively small number of markers would be needed for genome-wide LD mapping studies of this population. This population would be ideal for initial application of association studies using SNPs.
The limitations of a young founder population include the possibility that findings will not generalize to larger populations. Furthermore the extended LD, although helpful for initial gene mapping, may hamper fine mapping. Thus an ideal strategy for gene identification should include a coarse genome-wide scan in a very young founder population followed by fine mapping efforts in an older isolate or heterogenous population.
Wright has suggested that the choice of population in LD mapping studies is critical, particularly in the context of high disease allele frequencies and diversity (41). We support this contention and feel that it is important to collect detailed information on the population structure and genealogical history to maximally utilize founder populations for novel gene discoveries.
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ACKNOWLEDGEMENTS |
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We would like to thank the countless number of volunteers from Newfoundland who participated in this study. Furthermore we are indebted to Donna Hefferton, Hilary Vavasour, Neil Gladney, Judy Pinksen and Yvonne Tobin for their invaluable contribution. We also would like to acknowledge the help of the scientists at Gemini Genomics for input regarding the LD study. P.R. is supported by the Canadian Institute of Health Research and Arthritis Society of Canada for salary (CIHR New Investigator and TAS Scholar) and grant support. N.F. is supported by grants from the National Institutes of Health of the United States.
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FOOTNOTES |
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Newfound Genomics is a private genomics company based in Newfoundland. Sylvia Bartlett and Lynette Peddle are laboratory scientists at Newfound Genomics. Dr Rahman is a consultant to Newfound Genomics. No other authors have a conflict of interest regarding this manuscript. 
* To whom correspondence should be addressed at: St Clare's Mercy Hospital, Memorial University of Newfoundland, 1 South, 154 LeMarchant Rd, St John's, Newfoundland, Canada A1C 5B8. Tel: +1 7097775732; Fax: +1 7097775212; Email: prahman{at}mun.ca
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