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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 2001

• Hakonarson H et al. Allelic frequencies and patterns of single-nucleotide polymorphisms in candidate genes for asthma and atopy in Iceland. In Am J Respir Crit Care Med (164(11):2036-44). 2001.
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  Numerous asthma and atopy loci have been reported in studies demonstrating associations of the asthma-related phenotypes atopy, elevated IgE levels, and bronchial hyperresponsiveness with alleles of microsatellite markers and single-nucleotide polymorphisms (SNPs) within specific cytokine/chemokine and IgE-regulating genes. Although the studies reporting these observations are compelling, most of them lack statistical power. We assessed the nature, pattern, and frequency of SNPs in 24 candidate genes in Iceland and looked for associations with asthma and atopy. We identified 42 SNPs with an average minor allele frequency of 20.3% (asthma) and 20.7% (control). Twenty SNPs (48%) were within coding sequences and 90% of those led to a predicted change in protein sequence. No differences were detected in the allelic frequencies of SNPs in any of these candidate genes between control subjects and the patients with atopic asthma. Moreover, linkage analysis that included 269 patients with atopic asthma uncovered no evidence of linkage to markers associated with these genes. We conclude that this study has failed to produce evidence in support of the notion that variations within these 24 candidate atopy and asthma genes significantly influence the expression of the atopic asthmatic phenotype or contribute to the susceptibility of atopic asthma.

• Hakonarson H et al. Association between IL-1beta/TNF-alpha-induced glucocorticoid-sensitive changes in multiple gene expression and altered responsiveness in airway smooth muscle. In Am J Respir Cell Mol Biol (25(6):761-71). 2001.
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  The pleiotropic cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha have been implicated in the pathophysiology of asthma. To elucidate the role of these cytokines in the pro-asthmatic state, the effects of IL-1beta and TNF-alpha on airway smooth muscle (ASM) responsiveness and ASM expression of multiple genes, assessed by high-density oligonucleotide array analysis, were examined in the absence and presence of the glucocorticoid dexamethasone (DEX). Administration of IL-1beta/TNF-alpha increased ASM contractility to acetylcholine and impaired ASM relaxation to isoproterenol. These pro-asthmatic- like changes in ASM responsiveness were associated with IL-1beta/ TNF-alpha-induced mRNA expression of a host of proinflammatory genes that regulate transcription, cytokines and chemokines, cellular adhesion molecules, and various signal transduction molecules that regulate ASM responsiveness. In the presence of DEX, the changes induced in ASM responsiveness were abrogated, and most of the IL-1beta/TNF-alpha-mediated changes in proinflammatory gene expression were repressed, although mRNA expression of a small number of genes was enhanced by DEX. Collectively, the observations support the concept that, together with its role as a regulator of airway tone, in response to IL-1beta/TNF-alpha, the ASM expresses a host of glucocorticoid-sensitive genes that contribute to the altered structure and function of the airways in the pro-asthmatic state. We speculate that glucocorticoid-sensitive, cytokine-induced pathways involved in ASM cell signaling represent important targets for new therapeutic interventions.

• Ingvarsson T et al. A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p. In Arthritis Rheum (44(11):2548-55). 2001.
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  OBJECTIVE: To describe a large kinship with inherited hip osteoarthritis (OA) and its associated susceptibility locus. METHODS: Four generations of a kinship with familial hip OA were identified and characterized by family history and by clinical, radiographic, and histopathologic examination. In the genome-wide search for a susceptibility locus, OA cases were defined as those who had undergone total hip replacement associated with a clinical and radiographic diagnosis of hip OA. A genome-wide scan was performed using a framework set of microsatellite markers with an average spacing of 10 cM. RESULTS: The hip OA of this family was indistinguishable from that of idiopathic, nonfamilial hip OA. There was no apparent evidence of spondyloepiphyseal dysplasia or other dysplasias usually associated with mutations in collagen genes. The genome-wide scan revealed a locus on chromosome 16p between 28 cM and 47 cM from the telomere, and this locus met the criteria for suggestive linkage (multipoint allele-sharing logarithm of odds [LOD] score 2.58, P = 1.6 x 10(-4)). Two additional regions with LOD scores of >1.5 were obtained. CONCLUSION: We have identified and described the largest kinship with familial hip OA reported to date. Evidence for linkage in this family suggests that a gene for susceptibility to hip OA exists on chromosome 16p. This represents an independent identification of a susceptibility locus previously reported for hip OA in this geographic region.

• Olafsdottir BR et al. Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. In Neurology (57(10):1896-9). 2001.
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  The neuroexcitatory peptide hypocretin and its receptors are central to the pathophysiology of both human and animal models of the disease. In this study of American and Icelandic patients with narcolepsy, the authors found no significant association between narcolepsy and single-nucleotide polymorphisms in the genes for hypocretin or its two known receptors, hypocretin receptor-1 and hypocretin receptor-2.

• Stefansson H et al. Endometriosis is not associated with or linked to the GALT gene. In Fertil Steril (76(5):1019-22). 2001.
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  OBJECTIVE: To investigate a possible association between the carrier frequency of the N314D mutation in the galactose-1-phosphate uridyl transferase (GALT) gene and endometriosis and linkage to the short arm of chromosome 9, where the GALT gene resides. DESIGN: Association and linkage study. SETTING: Population material collected for case and family studies in endometriosis. PATIENT(S): Women diagnosed with endometriosis by laparotomy or laparoscopy. INTERVENTION(S): Association with the GALT gene investigated by genotyping 85 affected women and 213 unrelated control women and a scan for linkage to chromosome 9 in 205 women from 64 families with endometriosis. MAIN OUTCOME MEASURE(S): Multipoint parametric lod scores and frequency of alleles. RESULT(S): There was no significant difference in allele frequency for the N314D polymorphism in patients compared with control subjects. No evidence for linkage was found to chromosome 9p, where the GALT gene resides. CONCLUSION(S): The experiments reported herein provide no evidence supporting involvement of the GALT locus in the development of endometriosis.

• Grant SF et al. The inheritance of rheumatoid arthritis in Iceland. In Arthritis Rheum (44(10):2247-54). 2001.
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  OBJECTIVE: Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Although there is a large body of evidence suggesting that RA is immune mediated, the etiology remains unresolved. Twin studies have shown disease concordance rates of approximately 15% in monozygotic twins and 4% in dizygotic twins, while the estimated risk ratio for siblings of RA patients ranges from 5 to 8. Our goal was to use genealogic data from Iceland to further investigate the genetic component of RA. METHODS: Data were obtained from a population-based, computerized genealogy database that was developed to examine multigenerational relationships among individuals in the relatively homogeneous population of Iceland. Using an algorithm, the minimum founder test, we calculated the least number of founders required to account for a list of RA patients, and compared it with 1,000 sets of same-sized matched control groups. In addition, we estimated the kinship coefficient and risk ratios for relatives of the RA patients. RESULTS: Several familial clustering tests demonstrated that the RA patients were more related to each other than were the average control set of Icelanders. A significantly fewer number of founders was necessary to account for our patient list than for the random sets of matched controls (P < 0.001), and the average pairwise identity-by-descent sharing was greater among the patients than among the control sets (P < 0.001). In addition, there was an increased risk of RA in first- and second-degree relatives of the patients; e.g., for siblings, the risk ratio was 4.38 (95% confidence interval 3.26-5.67), and for uncles/aunts, the risk ratio was 1.95 (95% confidence interval 1.52-2.43). CONCLUSION: The familial component of RA is shown to extend beyond the nuclear family, thus providing stronger evidence for a significant genetic component to RA.

• Lachmeijer AM et al. A genome-wide scan for preeclampsia in the Netherlands. In Eur J Hum Genet (9(10):758-64). 2001.
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  Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.

• Gulcher J et al. The role of linkage studies for common diseases. In Curr Opin Genet Dev (11(3):264-7). 2001.
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  Linkage analysis when applied to common diseases has had limited success in mapping the genes contributing to them. We present a genealogic approach applied to the relatively isolated population of Iceland. We use an affecteds-only, allele-sharing method--which does not specify any particular inheritance model--implemented in the new statistical program, Allegro, which calculates lod scores based on multipoint calculations. We describe how this approach has helped us to map a gene contributing to the common late-onset form of Parkinson's disease to statistical significance.

• Hakonarson H, Wjst M. Current concepts on the genetics of asthma. In Curr Opin Pediatr (13(3):267-77). 2001.
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  Asthma is a complex genetic disorder with variable phenotype, largely attributed to the interactions of the environment and multiple genes, each potentially having small effects. Numerous asthma and atopy loci have been reported in studies demonstrating associations and/or linkage of the asthma-associated phenotypes, atopy, elevated IgE levels, and bronchial hyperresponsiveness to alleles of microsatellite markers and single nucleotide polymorphisms within specific cytokine/chemokine and IgE regulating genes. Although the studies reporting these observations are compelling, most of them lack statistical power. This review compiles the evidence that supports linkage and associations to the various genetic loci and candidate genes. Whereas significant progress has been made in the field of asthma genetics in the past decade, the roles of the genes and genetic variations within the numerous candidate asthma genes that have been found to associate with the expression of the asthmatic phenotype remain to be determined.

• Helgason A et al. mtDna and the islands of the North Atlantic: estimating the proportions of Norse and Gaelic ancestry. In Am J Hum Genet (68(3):723-37). 2001.
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  A total of 1,664 new mtDNA control-region sequences were analyzed in order to estimate Gaelic and Scandinavian matrilineal ancestry in the populations of Iceland, Orkney, the Western Isles, and the Isle of Skye and to investigate other aspects of their genetic history. A relative excess of private lineages in the Icelanders is indicative of isolation, whereas the scarcity of private lineages in Scottish island populations may be explained by recent gene flow and population decline. Differences in the frequencies of lineage clusters are observed between the Scandinavian and the Gaelic source mtDNA pools, and, on a continent-wide basis, such differences between populations seem to be associated with geography. A multidimensional scaling analysis of genetic distances, based on mtDNA lineage-cluster frequencies, groups the North Atlantic islanders with the Gaelic and the Scandinavian populations, whereas populations from the central, southern, and Baltic regions of Europe are arranged in clusters in broad agreement with their geographic locations. This pattern is highly significant, according to a Mantel correlation between genetic and geographic distances (r=.716). Admixture analyses indicate that the ancestral contributions of mtDNA lineages from Scandinavia to the populations of Iceland, Orkney, the Western Isles, and the Isle of Skye are 37.5%, 35.5%, 11.5%, and 12.5%, respectively.

• Gulcher J et al. The genealogic approach to human genetics of disease. In Cancer J (7(1):61-8). 2001.
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  The goal of modern human genetics is to correlate genes with disease or, more specifically, relate genetic variation to phenotypic variation. Although this correlation is usually straightforward in the Mendelian disorders, it has proved to be much more difficult to find in the common diseases because they appear to be more complex, likely involving an interplay among multiple genes and between genes and the environment. Although the strategy of linkage mapping of families was very successful when it was applied to the rare monogenic diseases, few common diseases have been mapped to statistical significance. Many investigators are now abandoning linkage analysis altogether and are moving to a candidate gene case-control strategy. In this article, we describe a genealogic approach to mapping human disease genes and provide three examples of how we have used it to map common diseases to statistical significance. We focus on a simple population with little historic migration and use a computerized genealogy database to increase the number of patients who can be compared with other affected relatives through high-density microsatellite genotyping. The genealogy helps determine which phenotypic classification is inherited and therefore possible to map. It may represent a more efficient strategy than candidate gene case-control studies for determination of what alleles or haplotypes are shared by patients in a population. We suggest that the genetics community not give up on linkage analysis, nor should it assume that the common diseases are too complex to map.