Hereditas 144: 171 180 (2007)
The genetic population structure of northern Sweden and its implications for mapping genetic diseases ELISABET EINARSDOTTIR1, INEZ EGERBLADH2, LARS BECKMAN1,$, DAN HOLMBERG1 and STEFAN A. ESCHER1 1Medical and Clinical Genetics, Dept. of Medical Biosciences, Umea˚ University, Umea˚, Sweden 2Centre for Population Studies, Umea˚ University, Umea˚, Sweden $Deceased 5 October 2005
Einarsdottir, E., Egerbladh, I., Beckman, L., Holmberg, D. and Escher, S. A. 2007. The genetic population structure of northern Sweden and its implications for mapping genetic diseases. * Hereditas 144: 171 180. Lund, Sweden. eISSN 1601- 5223. Received April 25, 2007. Accepted April 25, 2007
The northern Swedish population has a history of admixture of three ethnic groups and a dramatic population growth from a relatively small founder population. This has resulted in founder effects that together with unique resources for genealogical analyses provide excellent conditions for genetic mapping of monogenic diseases. Several recent examples of successful mapping of genetic factors underlying susceptibility to complex diseases have suggested that the population of northern Sweden may also be an important tool for efficient mapping of more complex phenotypes. A potential factor contributing to these effects may be population sub-isolates within the large river valleys, constituting a central geographic characteristic of this region. We here provide evidence that marriage patterns as well as the distribution of gene frequencies in a set of marker loci are compatible with this notion. The possible implications of this population structure on linkage- and association based strategies for identifying genes contributing risk to complex diseases are discussed.
Stefan A. Escher, Department of Molecular Biology, Umea˚ University, SE-901 87 Umea˚, Sweden. E-mail: stefan.a.escher@ molbiol.umu.se
Complex diseases have large repercussions on society, variants underlying complex phenotypes. To allow for but identification of the genetic risk factors underlying an optimal study design, it is thus important to them remains, in most cases, a major challenge. Large characterise in detail the population(s), revealing efforts and resources have been invested in this stratification possibilities and sub-isolates (HELGASON work, but the success rate to date has been limited et al. 2005). The population of northern Sweden has and most successful positional cloning projects been used extensively for genetic mapping of mono- focusing on complex diseases have been achieved genic diseases in particular (LUNDIN et al. 1997, using linkage-based approaches in populations with BURSTEDT et al. 1999, EINARSDOTTIR et al. 2004), reduced genetic heterogeneity (PELTONEN 1996, 2000, and lately also more complex traits (CARLSSON et al. SHEFFIELD et al. 1998, SHIFMAN and DARVASI 2001). 2002, VENKEN et al. 2005) and a detailed study of the More recently, large-scale association studies based population structure and hidden stratifications is on linkage disequilibrium (LD) mapping, made pos- essential to maximise future genetic mapping efforts sible through rapid technological development and in this population. efforts to establish a global haplotype map covering Northern Sweden is here defined as the two north- the genome, have come to light (HAPMAPPROJECT ernmost counties of Sweden, Va¨sterbotten and Norr- 2003). These efforts are likely to benefit from studies botten, with a total population of around 500 000 of different population isolates, due to their restricted individuals. Disease-mapping efforts in northern Swe- degree of genetic heterogeneity and extended regions den have been aided by several factors other than the of LD (JOHANSSON et al. 2005). genetic composition of the population itself. These Association-based mapping of genetic traits is include 1) a high-quality healthcare system, contribut- sensitive to hidden stratifications and confounding ing to a low frequency of undiagnosed cases and a factors within the population (BERGER et al. 2006), positive attitude towards genetic research; 2) large making accurate matching of controls essential to biobanks and disease registries further aiding the keep both false positive and false negative results to a study of diseases in this population; 3) a tradition of minimum. Founder effects and inbreeding may com- genealogical interest and comprehensive church regis- plicate association-based studies, but at the same time ters which have enabled the tracing of families to significantly reduce the genetic heterogeneity of a common founders and the identification of common population and aid in the identification of genetic founder mutations or haplotypes.
DOI: 10.1111/j.2007.0018-0661.02007.x 172 E. Einarsdottir et al. Hereditas 144 (2007)
Three main population-groups, Swedes, Finns and to a relative stability of the population from a genetic the Saami, make up the bulk of the northern Swedish point of view. population. The Saami are the endogenous population A number of genetic mapping projects have of northern Scandinavia, reaching northern Sweden provided evidence that founder effects, established as via Finland during the later Bronze Age. The Saami a result of the demographic history of the region, population lived in the inland areas of Sweden (SKO¨ LD underlie many of the diseases studied in the 2004), especially in the northernmost regions, but northern Swedish population (LUNDIN et al. 1997, became a minority group as the Swedes started to BURSTEDT et al. 1999, CARLSSON and FASTH 2001). move north. An early Finnish population settled down This, together with the geographic distribution of gene along the northern part of the Gulf of Bothnia, and frequencies of the disease-associated genes (BITTLES maintained frequent contacts with the population in and EGERBLADH 2005), suggests stratification in the northwestern Finland. A number of Finns also population and the potential existence of genetic sub- isolates. A plausible hypothesis, supported by histor- migrated to northern Sweden via the southeastern ical and demographic data, is that such sub-isolates parts of Sweden. A successive Swedish colonisation might have been formed in the large river valleys that took place in the coastal areas of northern Sweden, run from the mountains in the west to the coast in the strengthened by encouragements from the Swedish east and which are separated from each other by vast State in the early 14th century. It was not until forests. Each of these sub-isolates will have been much later, during the 19th century in particular, founded by different proportions of each of the three that colonisation took place in both the forested population-groups, contributing to initial differences areas near the coast and in the inland areas. In the of the sub-isolate populations (combined with the inland areas this process was characterised by an effects of genetic drift). However, each population will initial colonisation stemming from a relatively small subsequently have evolved into a distinct population, number of pioneers from the coastal parts within not characteristic for any of the three original the regions and from Finland, with subsequent population groups. settlements performed mainly by their descendants. Hence, immigration was small, and clusters of settle- ments representing several generations were formed METHODS (BYLUND 1960, 1994). To test the hypothesis that geographically defined sub- The size of the northern Swedish population was isolates exist in the population structure of northern around 15 000 16 000 in 1571. Most people lived in the Sweden, we divided Norrbotten and Va¨sterbotten coastal parts of the region, 13%, at most, in the inland. counties into regions based on the major rivers in Almost 200 years later, the region had only 36 000 the area. These rivers run from the mountains in the inhabitants according to the population sta- west of Sweden bordering Norway, to the eastern tistics in 1751 reliable at least for the non-Saami Swedish coast on the Bothnic Sea (Fig. 2). Five such population in the inland areas. The Saami population river valley regions were identified and a sixth region was nomadic and moved between districts and coun- represented an inland area located between two major tries, making it difficult to count even in late 18th rivers in Norrbotten. The population of each of these century (HOLLSTEN 1777). river valley regions is likely to be a unique mix of The relatively high fertility and low mortality, Finnish, Saami and Swedish genetic contributions, but however, resulted in a notable growth after 1750; an founder effects and subsequent inbreeding within each increase by 250% during the following century and small founder population could be hypothesised to another 274% to 1950 (Fig. 1). have resulted in a relatively homogeneous population Contribution from net in-migration from other within each river valley region. parts of Sweden was mainly a result of the large- scale exploitation of iron ore fields in region E and F Demographic studies from the turn of the 20th century, which also meant As a first approach to test the hypothesis that the main a decade of net in-migration on the county level river valleys in northern Sweden contain sub-isolates, 1871 1910 in contrast to the permanent net out- the frequencies of individuals choosing a spouse migration from Va¨sterbotten county observed at least within the same river valley region versus another in 1851 1970 (HOFSTEN and LUNDSTRO¨ M 1976). region were scored. For this purpose, we analysed the More than 90% of the population in late 20th marriages of the descendants of a couple that settled century in the northernmost regions was inborn in Lycksele in 1650. All recorded marriages from (SVERIGES NATIONALATLAS (SNA) 1991), testifying generations 1 4; and marriages in generations 5 9of Hereditas 144 (2007) Genetic population structure of northern Sweden 173
Region A 160 000 Region B 150 000 Region C Region D 140 000 Region E 130 000 Region F 120 000
110 000
100 000
90 000
80 000
70 000 Population 60 000
50 000
40 000
30 000
20 000
10 000
0 1571 1699 1751 1810 1830 1850 1870 1890 1910 1930 1950 1970 1990
Year
Fig. 1. The population growth of the population in northern Sweden from 1571 to 1990. Regions A to F refer to Fig. 2. the oldest child with descendants for each of the five bordering on Finland, and the other parent originated main branches of the family were studied. Descen- from Finland. In this case, the origin of the individual dants of individuals that moved from the region were was classified as region F. A total of 3887 individuals not traced further. A total of 1095 marriages were were used for this analysis. analysed. ABO, Rhesus and Duffy blood groups were deter- As a complement to the above approach, we also mined at the Umea˚ Blood bank by standard immu- analysed the marriage patterns of all married men nological analysis. 6-PGD and haptoglobin (Hp) aged between 40 and 50 and residing, in 1870 or polymorphisms were visualised by starch gel electro- 1900, in six parishes representing each of the river phoresis (FILDES and PARR 1963, BECKMAN and valley regions (chosen for completeness of data). GRIVEA 1964) and GC subtypes were determined by The Swedish census of 1870 and 1900 (available at immunoblotting after isoelectric focusing in a poly- www.svar.ra.se) was used. By means of this approach, acrylamide gel (CONSTANS et al. 1978). Polymorph- a total of 2986 marriages were analysed and the isms in transferrin (Tf) were visualised by isoelectric origins of husband and wife determined. focusing on a polyacrylamide gel (SIKSTROM et al. In addition to this, we looked at the origin of the 1988). Variants in PGM were determined according to wives of married men aged between 40 and 50 and the techniques compiled by GIBLETT (1969). born and residing in 1900 in six parishes (chosen for Allele frequencies in the six regions were plotted completeness of data). By means of this approach, a total of 1057 marriages were analysed. to visually assess geographic differences in the alleles or phenotypes of each marker. The SPSS 10 statistical software package was used to perform Study of genetic markers and geographic differences chi-square tests for each marker, comparing all or For genetic analysis of the population, a previously individual groups to determine statistically signifi- described cohort consisting of conscripts and blood cant differences in allele frequencies between the donors was used (BECKMAN et al. 1972, 1973). Only groups. individuals with both parents from the same river Fis and Fst values were obtained using the program valley region were used in the study. An exception to FSTAT (v2.9.3.2) (GOUDET 1995). Deviations from this was if one parent originated from region F, Hardy-Weinberg equilibrium (HWE) were examined 174 E. Einarsdottir et al. Hereditas 144 (2007)
Karesuando F Torn e river
Kalix river E Kiruna
Pajala D Lule rive Gällivare r
Jokkmokk
Pite river
Skell C efte river Ö-Kalix
B Vindeln river Arjeplog Kalix Luleå Tärnaby Ume river Älvsbyn
Arvidsjaur Piteå A
Ång Storuman erman river Skellefteå
Lycksele Vilhelmina
Åsele
Umeå
Fig. 2. The six river valley regions (A to F) that divide Va¨sterbotten and Norrbotten counties in northern Sweden. by comparing observed and expected gene frequencies chosen for this part of the study and followed over the in the markers PGM, Hp, Tf, GC and 6-PGD using time period 1650 1965. As illustrated in Fig. 3, FSTAT. throughout the period 1650 to 1950, the descendants predominantly married individuals originating from the same river valley region. Towards the end of this RESULTS period, the pattern changed, and in the time period Initially we tested the hypothesis that sub-isolates exist 1951 to 1965 more than 40% of the descendants in the river valleys in northern Sweden. To do this, we married individuals originating from another region. investigated the frequency with which individuals In accordance with previous reports that the peak of originating in a given river valley region chose a endogamous marriages in northern Sweden occurred spouse from within that region. Descendants of a around 1930 (BECKMAN and CEDERGREN 1971, couple settling in Lycksele (region B, Fig. 2) and BECKMAN et al. 1972), the change in marriage pattern previously identified as one of the largest founders of appeared to start after 1925. This has been suggested the population in the inland part of Ume river were to mainly be due to better communications within this Hereditas 144 (2007) Genetic population structure of northern Sweden 175
100
90
80
70
60
50
Percent (%) 40
30
20
10
0 1650- 1701- 1726- 1751- 1776- 1801- 1826- 1851- 1876- 1901- 1926- 1951- 1700 1725 1750 1775 1800 1825 1850 1875 1900 1925 1950 1965 Year of marriage Fig. 3. The frequency of marriages where both members were from the river valley region B (grey bars) and where only one member was from region B (black bars), as illustrated by a family traced from 1650 to 1965. region (BECKMAN and CEDERGREN 1971).The peak migrating to Ga¨llivare for work to marry amongst in marriages between different regions observed at the themselves and rather than people from Ga¨llivare is end of the 18th century can be explained historically supported by previous studies on marriage patterns by the colonisation process. in industrial settings in northern Sweden (WARG To evaluate to what extent these results were 2002), and supports the observation of a preference representative for the northern Swedish population towards spouses from the same river valley region. We as a whole, two groups of married men were analysed. conclude from this data that the observed preference As illustrated in Fig. 4, the proportion of marriages for marriages to spouses from the same region appears between different regions was around 10% in the to be a general phenomenon in the region at large. majority of the parishes in 1870. This had increased In order to exclude that this observation is merely in 1900, but remained below 20% in most of the the result of geographic clustering and not evidence for parishes. The large number of individuals from outside preferred selection of spouses within the entire river river valley region E marrying in Ga¨llivare in 1900 can valley region, we determined the origin of spouses of be explained by mining industry activities that began the married men living in Vilhelmina, Arvidsjaur, in Ga¨llivare in the late 1880s. The tendency of people Jokkmokk, Lycksele, Pajala and O¨ verkalix in 1900.
100
90
80
70
60
50 Percent (%) 40
30
20
10
0 1870 1900 1870 1900 1870 1900 1870 1900 1870 1900 1870 1900
VilhelminaVilhelmina Lycksele Lycksele Malå Malå Jokkmokk Jokkmokk Gällivare Gällivare Pajala Pajala
ABCDEF River valley regions A-F Fig. 4. Marriage patterns of six parishes that represent the six river valley regions (A to F). Married men, aged 40 50, and living in each of the six parishes in 1870 or 1900 were investigated. The origin of these men and their wives was noted as both being from the same river valley (grey bars), only one of them from that river valley (black bars) or both originating from another river valley (white bars). 176 E. Einarsdottir et al. Hereditas 144 (2007)
As expected from previous studies determining that variations are restricted by the river valley regions. geographic closeness constitutes an important An example of this is the ABO locus in which the gene factor with respect to choosing spouses (BECKMAN frequencies in river valley C significantly differ from and CEDERGREN 1971), a clear tendency was obser- that in the neighbouring regions B (south) and D ved among these men to marry within the parish (north). The PGM locus constitutes another example, (average 84.7%) (Table 1). Interestingly however, a the gene frequencies in region B being significantly clear preference for finding partners in neighbouring different from those in region A and C. parishes within the same river valley region (average Significant deviations from Hardy-Weinberg equili- 8.4%) over partners originating in neighbouring brium were only found in region B for the marker parishes but outside of the river valley region (average 6-PGD (p-value 0.021), but two out of five markers 3.4%), was also noted. deviated significantly from HWE in the total popula- The demographic data obtained from analysing tion (6PGD p-value 0.045 and PGM p-value 0.01). Fis marriage patterns supports the notion that the river and Fst values did not indicate high levels of inbreed- valley regions represent genetic sub-isolates within ing (Fis, range of p-values from 0.11 to 0.74 per the northern Swedish population. To test for impact population) or differentiation (Fst, range of values of this on the genetic differentiation between the from 0.001 to 0.013 per locus), but these values are regions, we took advantage of a previous study in rarely high in natural populations, and the relatively which eight polymorphic protein markers had pre- low degree of polymorphism in the markers used may viously been analysed in a large cohort representative not be optimal for this analysis. of this population (BECKMAN et al. 1972) (Table 2). The markers were originally chosen to study ethnic heterogeneity in the northern Swedish population and DISCUSSION were used to demonstrate the impact of ethnic The population of northern Sweden constitutes one heterogeneity on genetic disorders such as hypercho- example of an ‘‘isolated’’ population that has been lesterolemia (NYLANDER et al. 1993). The original used extensively for mapping genetic diseases. Taking data was re-analysed under the hypothesis that geno- advantage of such populations has proven efficient for type distribution would correlate to the 6 river valley positional cloning of monogenic diseases. More re- regions defined in Fig. 2. cently, the reduced genetic heterogeneity in such The distributions of gene frequencies for several of populations has also been argued to provide an the 8 loci were previously reported to support the important advantage in linkage- and association- notion of a gradient in accordance with the expected based studies aimed at identifying susceptibility genes patterns of Finnish and Saami admixture (BECKMAN contributing to complex diseases (DE LA CHAPELLE et al. 1988a, b, NYLANDER et al. 1988, SIKSTROM et al. and WRIGHT 1998, RAHMAN et al. 2003, BLANGERO 1988, NYLANDER and BECKMAN 1991). This can be 2004, VARILO and PELTONEN 2004). To set optimal seen in the markers GC, 6-PGD and Tf, where regions conditions for such studies, it is essential that con- E and F (likely to have a higher proportion of Finnish founding factors such as admixture of different genetic material) significantly differ from regions A population groups and the existence of possible sub- to D. As illustrated in Fig. 5 and Table 3 however, an isolates leading to genetic stratification are well additional trend suggests regional gene frequency characterised in the population under investigation.
Table 1. The origin of wives of married men, aged 40 50, and living in six different parishes in 1900. Numbers indicate the number of marriages (percentage in brackets).
Vilhelmina Lycksele Arvidsjaur Jokkmokk O¨ verkalix Pajala Total
Same parish 225 (94.1) 186 (83.0) 135 (84.4) 56 (75.7) 194 (89.8) 117 (81.3) 913 (84.7) Neighbouring parish 4 (1.7) 22 (9.8) 21 (13.1) 10 (13.5) 13 (6.0) 9 (6.3) 79 (8.4) within rivervalley region Other parish within 0 (0) 1 (0.4) 0 (0) 0 (0) 2 (0.9) 9 (6.3) 12 (1.3) rivervalley region Neighbouring parish 4 (1.7) 12 (5.4) 0 (0) 8 (10.8) 5 (2.3) 0 (0) 29 (3.4) outside rivervalley region Other regions 6 (2.5) 3 (1.3) 4 (2.5) 0 (0) 2 (0.9) 9 (6.3) 24 (2.3) Total 239 224 160 74 246 144 1057 Hereditas 144 (2007) Genetic population structure of northern Sweden 177
Table 2. The blood groups and protein markers used for regions, indicating that these regions do indeed con- the analysis of regional differences in allele frequencies. stitute distinct genetic sub-isolates. The observed stratification may be of particular Marker Alleles/ Marker name phenotypes importance to studies based on the extent of LD and on efforts such as the HAPMAPPROJECT (2003). Since PGM 1, 2 phosphoglucomutase it has previously been shown that isolated, recently Hp 1, 2 haptoglobin admixed populations tend to have larger regions ABO A, B, O ABO blood group phenotype of LD (JOHANSSON et al. 2005), considerably fewer Rh Pos, neg Rhesus blood group haplotype-tagging single-nucleotide polymorphism phenotype (SNPs) may be needed for genetic analysis of each Tf 1, 2, 3 transferrin, iron transporting sub-isolate. While these observations demonstrate the serum protein importance of careful sub-regional matching in asso- GC 1F, 1S, 2 group-specific component, vitamin-D binding serum ciation-based studies performed on the northern protein Swedish population, it is clear that more quantitative Fya Pos, neg Duffy blood group, presence data illustrating the extent of genetic variation be- phenotype of allele a tween regions is needed to make such optimal match- 6-PGD A, C 6-phosphogluconate ing possible. dehydrogenase The stratification and existence of distinct sub- isolates within the population may also have implica- tions on linkage-based strategies for identifying The present study has provided evidence that in susceptibility genes in complex diseases. Thus, the addition to known admixture of three ethnic groups, genetic admixture of the total population might Saami, Swedes and Finns, each of the larger river locally be negated by an increase in genetic homo- valleys in northern Sweden contains distinct genetic geneity, and susceptibility alleles may be significantly sub-isolates. These sub-isolates arose by preferential increased or decreased in a given sub-isolate. Such contact between individuals within the regions. In effects may enhance the founder effects underlying line with this, we demonstrate a tendency towards several monogenic diseases as well as contribute to an marriages between individuals born in the same increase in the occurrence of familial forms of river valley region, at least until the mid 20th century. complex diseases. This scenario predicts that familial This demographic pattern is reflected in the distinct forms of complex diseases should cluster geographi- genetic differences between adjacent river valley cally into some of the river valley regions, while being
100
90
80
70 GC-2 60 HP-1 ABO-A
of allele PGM-1 50
ncy Fya-pos
que Rh-pos 40 Tf-1
Fre 6-PGD-A 30
20
10
0 A B C D E F River valley region (A in south, F in north)
Fig. 5. The frequency of alleles or phenotypes in percent of each of the eight protein markers re-analysed to assess genetic variation between each of the six river valley regions (A to F). 178
Chi-square analysis of differences in allele frequencies between the six river valley regions. Each region is compared to the other regions; shaded areas
Table 3. al. et Einarsdottir E. indicate significant differences, where pB0.05.
PGM B C D E F Gc B C D E F
A B0.0001 0.16 0.04 0.26 0.1 A 0.79 0.49 0.39 0.0002 0.009 B 0.04 0.24 0.45 0.005 B 0.31 0.07 B0.0001 B0.0001 C 0.41 0.9 0.1 C 0.22 B0.0001 B0.0001 D 0.78 0.05 D B0.0001 B0.0001 E 0.54 E 0.09 F F AvsBvsCvsDvsEvsF AvsBvsCvsDvsEvsF p 0.1 p B0.0001 Tf B C D E F 6-PGD B C D E F
A 0.06 0.02 0.26 0.002 B0.0001 A 0.12 0.17 0.33 0.005 0.02 B 0.35 0.63 0.01 0.001 B 0.65 0.4 0.02 0.03 C 0.21 0.002 B0.0001 C 0.57 0.007 0.01 D 0.02 0.004 D 0.01 0.03 E 0.78 E 0.37 F F AvsBvsCvsDvsEvsF AvsBvsCvsDvsEvsF p B0.0001 p 0.003 Fya B C D E F Hp B C D E F
A 0.07 0.05 B0.0001 0.07 0.01 A 0.07 0.36 0.37 0.11 0.09 B 0.79 0.002 0.64 0.2 B 0.11 0.34 0.69 0.96 C 0.003 0.74 0.26 C 0.89 0.24 0.17 D 0.12 0.05 D 0.33 0.38 E 0.78 E 0.69 AvsBvsCvsDvsEvsF AvsBvsCvsDvsEvsF p 0.005 p 0.28 Rh B C D E F ABO B C D E F
A 0.12 0.95 0.2 0.04 0.11 A 0.27 0.17 0.001 0.11 0.03 B 0.008 0.95 0.22 0.81 B 0.02 0.001 0.24 0.03 C 0.08 0.01 0.01 C B0.0001 0.005 B0.0001
D 0.25 0.81 D 0.53 0.28 (2007) 144 Hereditas E 0.28 E 0.92 AvsBvsCvsDvsEvsF AvsBvsCvsDvsEvsF p 0.01 p 0.007
p or less than 0.05. Hereditas 144 (2007) Genetic population structure of northern Sweden 179 rare in others. While sub-isolates formed in this Constans, J., Viau, M., Cleve, H. et al. 1978. Analysis of the manner may make association-based studies more Gc polymorphism in human populations by isoelectro- difficult, this potentially makes the mapping of focusing on polyacrylamide gels. Demonstration of sub- types of the Gc allele and of additional Gc variants. genetic diseases of individuals within the same Hum. Genet. 41: 53 60. genetic sub-population more powerful. De La Chapelle, A. and Wright, F. A. 1998. Linkage disequilibrium mapping in isolated populations: the Acknowledgements The authors wish to thank Solveig example of Finland revisited. Proc. Natl Acad. Sci. Linghult and Carin Sikstro¨m for assistance in computerising USA 95: 12416 12423. the protein marker material and Petter Lindgren for help Einarsdottir, E., Carlsson, A., Minde, J. et al. 2004. A with the statistical analysis. We thank Sven-Erik Fahlesson mutation in the nerve growth factor beta gene (NGFB) for providing us with access to his genealogical database. causes loss of pain perception. Hum. Mol. Genet. 13: 799 805. Fildes, R. A. and Parr, C. W. 1963. Human red- REFERENCES cell phosphogluconate dehydrogenases. Nature 200: 890 891. Beckman, L. and Grivea, M. 1964. Haptoglobin variations Giblett, E. R. 1969. Genetic markers in human blood. in newborn children. Acta Genet. Stat. Med. 14: 159 Blackwell. 167. Goudet, J. 1995. FSTAT (ver. 1.2): a computer program to Beckman, L. and Cedergren, B. 1971. Population studies in calculate F-statistics. J. Hered. 86: 485 486. Northern Sweden. I. Variations of matrimonial migration HapmapProject 2003. The international HapMap Project. distances in time and space. Hereditas 68: 137 142. Nature 426: 789 796. Beckman, L., Cedergren, B., Collinder, E. et al. 1972. Helgason, A., Yngvadottir, B., Hrafnkelsson, B. et al. 2005. Population studies in northern Sweden. III. Variations An Icelandic example of the impact of population of ABO and Rh blood group gene frequencies in time and structure on association studies. Nat. Genet. 37: 90 95. space. Hereditas 72: 183 200. Hofsten, E. and Lundstro¨m, H. 1976. Swedish population Beckman, L., Cedergren, B. and Rasmuson, M. 1973. history. Main trends from 1750 to 1970, Urval. Skrift- Population studies in northern Sweden. V. Regional serier utgiven av Statistiska Centralbyra˚n, no. 8. heterogeneity of the A 2 blood group gene frequency. Hollsten, J. 1777. Folk-numern uti na˚gra Fo¨rsamlingar I Hereditas 73: 253 258. Svenska Lappmarken, med Anma¨rkningar om Lappska Beckman, L., Beckman, G. and Nylander, P. O. 1988a. Gc Allmogens lefnads-sa¨tt samt til- eller aftagande, Kongl. subtypes in Finns, Swedes and Swedish Lapps. Hum. Vetenskaps-Academiens Handlingar 38:1, 44 52. Hered. 38: 18 21. Johansson, A., Vavruch-Nilsson, V., Edin-Liljegren, A. et al. Beckman, L., Beckman, G. and Nylander, P. O. 1988b. Population studies in northern Sweden. XIII. The 2005. Linkage disequilibrium between microsatellite 6-phosphogluconate dehydrogenase polymorphism. markers in the Swedish Sami relative to a worldwide Hum. Hered. 38: 168 173. selection of populations. Hum. Genet. 116: 105 113. Berger, M., Stassen, H. H., Kohler, K. et al. 2006. Hidden Lundin, G., Lee, J. S., Thunell, S. et al. 1997. Genetic population substructures in an apparently homogeneous investigation of the porphobilinogen deaminase gene in population bias association studies. Eur. J. Hum. Genet. Swedish acute intermittent porphyria families. Hum. 14: 236 244. Genet. 100: 63 66. Bittles, A. and Egerbladh, I. 2005. The influence of past Nylander, P. O. and Beckman, L. 1991. Population studies in endogamy and consanguinous marriages on genetic northern Sweden. XVII. Estimates of Finnish and disorders in Northern Sweden. Ann. Hum. Genet. 69: Saamish influence. Hum. Hered. 41: 157 167. 1 10. Nylander, P. O., Beckman, L. and Cedergren, B. 1988. Blangero, J. 2004. Localization and identification of human Population studies in northern Sweden. XIV. Variation of quantitative trait loci: king harvest has surely come. the A1A2B0 blood group gene frequencies. Hum. Curr. Opin. Genet. Dev. 14: 233 240. Hered. 38: 291 302. Burstedt, M. S., Sandgren, O., Holmgren, G. et al. 1999. Nylander, P. O., Asplund, K., Beckman, L. et al. 1993. Bothnia dystrophy caused by mutations in the cellular Population studies in northern Sweden. 18. Geographical retinaldehyde-binding protein gene (RLBP1) on chromo- covariation between hypercholesterolemia and Finnish some 15q26. Invest. Ophthalmol. Vis. Sci. 40: 995 1000. genetic influence. Hum. Hered. 43: 147 154. Bylund, E. 1960. Theoretical considerations regarding the Peltonen, L. 1996. Identification of disease genes in genetic distribution of settlement in inner north Sweden. isolates. Methods 9: 129 135. Geografiska Annaler. 53: 225 231. Peltonen, L. 2000. Positional cloning of disease genes: Bylund, E. 1994. Koloniseringen av Botnia-regionen. advantages of genetic isolates. Hum Hered. 50: 66 75. Bokfo¨rlaget Bra Bo¨cker. Rahman, P., Jones, A., Curtis, J. et al. 2003. The Newfound- Carlsson, A., Forsgren, L., Nylander, P. O. et al. 2002. land population: a unique resource for genetic investiga- Identification of a susceptibility locus for migraine with tion of complex diseases. Hum. Mol. Genet. 12 Spec and without aura on 6p12.2 p21.1. Neurology 59: No. 2, R167 172. 1804 1807. Sheffield, V. C., Stone, E. M. and Carmi, R. 1998. Use of Carlsson, G. and Fasth, A. 2001. Infantile genetic agranu- isolated inbred human populations for identification of locytosis, morbus Kostmann: presentation of six cases disease genes. Trends Genet. 14: 391 396. from the original ‘‘Kostmann family’’ and a review. Shifman, S. and Darvasi, A. 2001. The value of isolated Acta Paediatr 90: 757 764. populations. Nat. Genet. 28: 309 310. 180 E. Einarsdottir et al. Hereditas 144 (2007)
Sikstrom, C., Nylander, P. O. and Beckman, L. 1988. Venken, T., Claes, S., Sluijs, S. et al. 2005. Genomewide scan Population studies in northern Sweden. XV. Transferrin for affective disorder susceptibility loci in families of a C subtypes. Hum. Hered. 38: 341 352. northern Swedish isolated population. Am. J. Hum. Sko¨ld, P. 2004. Liv och do¨d i Lappmarken. Aspekter pa˚ Genet. 76: 237 248. den geografiska utvecklingen i Arjeplog under 1700- och Warg, S. 2002. Migrating to mining-industrialisation, migra- 1800-talen. In: Lantto, P. and Sko¨ld, P. (eds), Befolkn- tion and regional development in the Norrbotten mining ing och bosa¨ttning i norr. Etnicitet, identitet och gra¨nser i district at the turn of the 20th century. Subarctic Mining historiens sken. Skrifter fra˚n Centrum fo¨r samisk for- II. Jernkontorets Bergshistoriska Utskott H72, Lulea˚, skning 1: 85 105. Sweden. Sveriges Nationalatlas (Sna) 1991. Befolkningen, Bokfo¨rla- get Bra Bo¨cker. Varilo, T. and Peltonen, L. 2004. Isolates and their potential use in complex gene mapping efforts. Curr. Opin. Genet. Dev. 14: 316 323.