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Browse through the publications and recorded discoveries from deCODE that have appeared in highly regarded journals around the world.

Publications by deCODE scientists in 2000

• Gulcher J et al. Genetic homogeneity of Icelanders. In Nat Genet (26(4):395). 2000.
  
• Ingvarsson T et al. The inheritance of hip osteoarthritis in Iceland. In Arthritis Rheum (43(12):2785-92). 2000.
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  OBJECTIVE: To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis (OA) leading to total hip replacement (THR). METHODS: Information from 2 population-based databases in Iceland was combined: a national registry of all THRs performed between 1972 and 1996, and a genealogy database of all available Icelandic genealogy records for the last 11 centuries. A genetic contribution to THR for OA was assessed by 1) identifying familial clusters of OA patients with THR, 2) applying the minimum founder test (MFT) to estimate the minimum number of ancestors ("founders") that would account for the genealogy of all 2,713 patients with THR for OA, compared with the average number of founders for control lists, 3) calculating an average pairwise kinship coefficient (KC) for the patient list and control lists, and 4) estimating the relative risk (RR) for THR among relatives of OA patients who have undergone the procedure. One thousand matched control lists, each the same size as the patient list, were created using the genealogy database. RESULTS: A large number of familial clusters of patients with THR for OA were identified. The MFT showed that OA patients descended from fewer founders than did subjects in the control groups (P < 0.001). The average pairwise KC among patients with OA was greater than in the control population (P < 0.001). The RR for THR among siblings of OA patients was 3.05 (95% confidence interval 2.52-3.10). CONCLUSION: This population-based study shows that Icelandic patients with hip replacement for OA are significantly more related to each other than are matched controls drawn from the Icelandic population. These findings support a significant genetic contribution to a common form of OA and encourage the search for genes conferring an increased susceptibility to OA.

• Sveinbjornsdottir S et al. Familial aggregation of Parkinson's disease in Iceland. In N Engl J Med (343(24):1765-70). 2000.
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  BACKGROUND: The role of genetics in early-onset Parkinson's disease has been established, but whether there is a genetic contribution to the more common, late-onset form remains uncertain. METHODS: We reviewed the medical records and confirmed the diagnosis of Parkinson's disease in 772 living and deceased patients in whom the disease had been diagnosed during the previous 50 years in Iceland. With the use of an extensive computerized data base containing genealogic information on 610,920 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than random members of the population (control subjects). RESULTS: Patients with Parkinson's disease, including a subgroup of 560 patients with late-onset disease (onset at >50 years of age), were significantly more related to each other than were subjects in matched groups of controls, and this relatedness extended beyond the nuclear family. The risk ratio for Parkinson's disease was 6.7 (95 percent confidence interval, 4.3 to 9.6) for siblings, 3.2 (95 percent confidence interval, 1.2 to 7.8) for offspring, and 2.7 (95 percent confidence interval, 1.6 to 3.9) for nephews and nieces of patients with late-onset Parkinson's disease. CONCLUSIONS: Late-onset Parkinson's disease has a genetic component as well as an environmental component.

• Kong A, Nicolae D. On a randomization procedure. In Am J Hum Genet (67(5):1352-6). 2000.
  
• Grant SF et al. Long PCR detection of the C4A null allele in B8-C4AQ0-C4B1-DR3. In J Immunol Methods (244(1-2):41-7). 2000.
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  The genes coding for the two components of complement 4 (C4), C4A and C4B, are located within the major histocompatibility complex (MHC) on the short arm of chromosome 6. Several studies have shown that deficiency of C4A is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma. A large deletion covering most of the C4A gene and the 21-hydroxylase-A (21-OHA) pseudogene found on the extended haplotype B8-C4AQ0-C4B1-DR3 is estimated to account for approximately two-thirds of C4A deficiency in Caucasian SLE patients. Detection of this C4A null allele has been technically difficult due to the high degree of homology between C4A and C4B, with protein analysis and restriction fragment length polymorphism (RFLP) analysis using Southern blotting being the only approaches available. In this study, a long PCR strategy was used to rapidly genotype for the C4A deletion through specific primer design. The methodology makes use of the unique sequence of the G11 gene upstream of C4A and the sequence of a 6.4 kb retrotransposon, the human endogenous retrovirus HERV-K(C4), which is present in intron 9 of C4A but absent in the case of the deletion.

• Gudmundsson H et al. Inheritance of human longevity in Iceland. In Eur J Hum Genet (8(10):743-9). 2000.
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  The idea that human longevity is influenced by genetic factors has recently received strong support from work on other species. On the basis of partial population studies and selected kinships, significant correlations between the ages of parents and offspring have been reported, and some but not all twin studies have confirmed that human longevity is moderately inherited. However, studies based upon a relatively small proportion of a population are susceptible to sampling error and selection bias. Here we report the use of a comprehensive population-based computerised genealogy database to examine multigenerational relationships among those who live to the 95th percentile in Iceland. We have developed a clustering tool which can generate large extended pedigrees connecting individuals from any list using the genealogy database. First degree relatives of those living to the 95th percentile are almost twice as likely to live to the 95th percentile compared with controls. Furthermore, we have developed an algorithm which we have named the Minimum Founder Test (MFT) to examine the degree of relatedness of any population-based list of individuals to estimate whether a trait has a familial component. The data indicate that there is a significant genetic component to longevity. In addition, age-specific death rates are significantly lower in the offspring of long-lived parents compared with controls, especially after age 70.

• Gulcher J et al. Protection of privacy by third-party encryption in genetic research in Iceland. In Eur J Hum Genet (8(10):739-42). 2000.
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  As the new human genetics continues its dramatic expansion into many laboratories and medical institutions, the concern for the protection of the personal privacy of individuals who participate increases. It seems that even the smallest of laboratories must confront the issue of how to protect the genetic and phenotypic information of participants in their research. Some have promoted the use of anonymity as a way out of this dilemma. But we are reminded by others that the future cannot be predicted, and that future benefits may be lost when the links to these benevolent volunteers are gone forever. More recently, some ethical bodies have suggested, without specific recommendations, that a reversible third-party encryption system may be a solution to this problem. However, they have not provided a route or even examples of how to proceed. We present here the Icelandic approach to this issue by developing a third-party encryption system in direct collaboration with the Data Protection Commission (DPC) of Iceland. We have incorporated the encryption system within our sample collection and storage software, which minimises inconvenience but enhances security. The strategy assures a barrier between the laboratory and the outside world that can only be crossed by the DPC.

• Helgason A et al. Estimating Scandinavian and Gaelic ancestry in the male settlers of Iceland. In Am J Hum Genet (67(3):697-717). 2000.
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  We present findings based on a study of Y-chromosome diallelic and microsatellite variation in 181 Icelanders, 233 Scandinavians, and 283 Gaels from Ireland and Scotland. All but one of the Icelandic Y chromosomes belong to haplogroup 1 (41.4%), haplogroup 2 (34.2%), or haplogroup 3 (23.8%). We present phylogenetic networks of Icelandic Y-chromosome variation, using haplotypes constructed from seven diallelic markers and eight microsatellite markers, and we propose two new clades. We also report, for the first time, the phylogenetic context of the microsatellite marker DYS385 in Europe. A comparison of haplotypes based on six diallelic loci and five microsatellite loci indicates that some Icelandic haplogroup-1 chromosomes are likely to have a Gaelic origin, whereas for most Icelandic haplogroup-2 and -3 chromosomes, a Scandinavian origin is probable. The data suggest that 20%-25% of Icelandic founding males had Gaelic ancestry, with the remainder having Norse ancestry. The closer relationship with the Scandinavian Y-chromosome pool is supported by the results of analyses of genetic distances and lineage sharing. These findings contrast with results based on mtDNA data, which indicate closer matrilineal links with populations of the British Isles. This supports the model, put forward by some historians, that the majority of females in the Icelandic founding population had Gaelic ancestry, whereas the majority of males had Scandinavian ancestry.

• Gulcher J, Stefansson K. Guest Editorial - The Icelandic Healthcare Database: A Tool to Create Knowledge, A Social Debate, and a Bioethical and Privacy Challenge. In Medscape. 2000.
  
• Gulcher J, Stefansson K. The Icelandic Healthcare Database and informed consent. In N Engl J Med (342(24):1827-30). 2000.
  
• Gudbjartsson DF et al. Allegro, a new computer program for multipoint linkage analysis. In Nat Genet (25(1):12-3). 2000.
  
• Sigurdardottir S et al. The mutation rate in the human mtDNA control region. In Am J Hum Genet (66(5):1599-609). 2000.
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  The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation rate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA mutation rates on the basis of pedigrees, and the estimated mutation rate is intermediate among those derived from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.

• Helgason A et al. mtDNA and the Origin of the Icelanders: Deciphering Signals of Recent Population History. In Am J Hum Genet (66(3):999-1016). 2000.
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  Previous attempts to investigate the origin of the Icelanders have provided estimates of ancestry ranging from a 98% British Isles contribution to an 86% Scandinavian contribution. We generated mitochondrial sequence data for 401 Icelandic individuals and compared these data with >2,500 other European sequences from published sources, to determine the probable origins of women who contributed to Iceland's settlement. Although the mean number of base-pair differences is high in the Icelandic sequences and they are widely distributed in the overall European mtDNA phylogeny, we find a smaller number of distinct mitochondrial lineages, compared with most other European populations. The frequencies of a number of mtDNA lineages in the Icelanders deviate noticeably from those in neighboring populations, suggesting that founder effects and genetic drift may have had a considerable influence on the Icelandic gene pool. This is in accordance with available demographic evidence about Icelandic population history. A comparison with published mtDNA lineages from European populations indicates that, whereas most founding females probably originated from Scandinavia and the British Isles, lesser contributions from other populations may also have taken place. We present a highly resolved phylogenetic network for the Icelandic data, identifying a number of previously unreported mtDNA lineage clusters and providing a detailed depiction of the evolutionary relationships between European mtDNA clusters. Our findings indicate that European populations contain a large number of closely related mitochondrial lineages, many of which have not yet been sampled in the current comparative data set. Consequently, substantial increases in sample sizes that use mtDNA data will be needed to obtain valid estimates of the diverse ancestral mixtures that ultimately gave rise to contemporary populations.