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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 2003

• Blondal T et al. A novel MALDI-TOF based methodology for genotyping single nucleotide polymorphisms. In Nucleic Acids Res (31(24):e155). 2003.
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  A new MALDI-TOF based detection assay was developed for analysis of single nucleotide polymorphisms (SNPs). It is a significant modification on the classic three-step minisequencing method, which includes a polymerase chain reaction (PCR), removal of excess nucleotides and primers, followed by primer extension in the presence of dideoxynucleotides using modified thermostable DNA polymerase. The key feature of this novel assay is reliance upon deoxynucleotide mixes, lacking one of the nucleotides at the polymorphic position. During primer extension in the presence of depleted nucleotide mixes, standard thermostable DNA polymerases dissociate from the template at positions requiring a depleted nucleotide; this principal was harnessed to create a genotyping assay. The assay design requires a primer- extension primer having its 3'-end one nucleotide upstream from the interrogated site. The assay further utilizes the same DNA polymerase in both PCR and the primer extension step. This not only simplifies the assay but also greatly reduces the cost per genotype compared to minisequencing methodology. We demonstrate accurate genotyping using this methodology for two SNPs run in both singleplex and duplex reactions. We term this assay nucleotide depletion genotyping (NUDGE). Nucleotide depletion genotyping could be extended to other genotyping assays based on primer extension such as detection by gel or capillary electrophoresis.

• Giedraitis V et al. Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q. In Genes Immun (4(8):559-63). 2003.
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  Epidemiological studies show that susceptibility to multiple sclerosis (MS) has a strong genetic component, but apart from the HLA gene complex, additional genetic factors have proven difficult to map in the general population. Thus, localized populations, where MS patients are assumed to be more closely related, may offer a better opportunity to identify shared chromosomal regions. We have performed a genome-wide scan with 834 microsatellite markers in a data set consisting of 54 MS patients and 114 healthy family members. A group of families from a small village were possible to track back to common ancestors living in the 17th century. We used single marker- and haplotype-based transmission disequilibrium test (TDT) analysis and nonparametric linkage analysis to analyze genotyping data. Regions on chromosomes 2q23-31, 6p24-21, 6q25-27, 14q24-32, 16p13-12 and 17q12-24 were found to be in transmission disequilibrium with MS. Strong transmission disequilibrium was detected in 14q24-32, where several dimarker haplotypes were in transmission disequilibrium in affected individuals. Several regions showed modest evidence for linkage, but linkage and TDT were both clearly positive only for 17q12-24. All patients and controls were also typed for HLA class II genes; however, no evidence for a gene-gene interaction was observed.

• Styrkarsdottir U et al. Linkage of osteoporosis to chromosome 20p12 and association to BMP2. In PLoS Biol (1(3):E69). 2003.
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  Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 x 10(-7)), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes.

• Bjornsson A et al. Localization of a gene for migraine without aura to chromosome 4q21. In Am J Hum Genet (73(5):986-93). 2003.
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  Migraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genome-wide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6)).

• Gretarsdottir S et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. In Nat Genet (35(2):131-8). 2003.
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  We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

• Helgason A, Stefansson K. Erroneous claims about the impact of mitochondrial DNA sequence database errors. In Am J Hum Genet (73(4):974-5). 2003.
  
• Jonasdottir A et al. A whole genome association study in Icelandic multiple sclerosis patients with 4804 markers. In J Neuroimmunol (143(1-2):88-92). 2003.
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  Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) with a complex genetic background. Here we use a genome-wide association strategy with 4804 microsatellite markers successfully typed in separately pooled DNA from 200 patients and 200 controls. A total of 91 markers showed evidence of association. When compared to our in-house physical map of the genome, six 2-Mb regions containing at least two of these markers were detected. Of those, three regions have one or more markers among the 20 most strongly associated: chromosomes 3q25, 6p21.3 (the MHC region) and 19q13.

• Laaksonen M et al. A whole genome association study in Finnish multiple sclerosis patients with 3669 markers. In J Neuroimmunol (143(1-2):70-3). 2003.
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  Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with complex genetic background. In the present study, based in the Finnish population, we typed a large number of microsatellite markers in separately pooled DNA samples from 195 MS patients and 205 controls. A total of 108 markers showed evidence of association. Five genomic regions containing two or more of these markers within a 1-Mb interval were identified, 1q43, 2p16, 4p15, 4q34 and 6p21 (the MHC region). Substantial overlap with previously published linkage genome screens is also seen.

• Martins Silva B et al. A whole genome association study in multiple sclerosis patients from north Portugal. In J Neuroimmunol (143(1-2):116-9). 2003.
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  Genetic factors are known to influence susceptibility to multiple sclerosis (MS) but the genes involved are largely undefined. Here, we report an association study based on 200 patients and 200 controls from the Porto region in Portugal. A total of 3974 markers were successfully typed from which we have identified 46 markers showing evidence of association. When compared to a physical map three regions were found with two of these markers less than 1.5 Mb apart: chromosomes 6p21.3 (the MHC region), 6q14.1 and 7q34.

• Reynisdottir I et al. Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35,2. In Am J Hum Genet (73(2):323-35). 2003.
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  We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 2.90, P=1.29 x 10(-4)) in all diabetics. Since obesity, here defined as body mass index (BMI) > or =30 kg/m(2), is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI > or =30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 3.64, P=2.12 x (10)-5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12 x 10(-5)) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.

• Helgason A et al. A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift. In Ann Hum Genet (67(Pt 4):281-97). 2003.
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  There has been some controversy in the literature concerning whether Icelanders are genetically homogenous or heterogeneous relative to other European populations. We reassess this question in the light of large data sets spanning 83 autosomal SNP loci, 14 serogenetic loci, 6622 Y-chromosomes and 3214 sequences from mtDNA hypervariable segments 1 and 2 (HVS1 and HVS2). Our results strongly support the hypothesis that genetic drift, with a consequent loss of variation, has had a greater impact on Icelanders than most other Europeans. We also analyse 7245 HVS1 sequences from 25 European populations. In line with other studies, we observe a deficit of rare HVS1 haplotypes and an excess of intermediate frequency haplotypes in Icelanders compared to most European populations, with some measures of genetic diversity indicating relative heterogeneity and others indicating relative homogeneity of Icelanders. Simulations indicate that genetic drift, and not admixture (as proposed by Arnason, 2003) is the most likely cause of the atypical Icelandic HVS1 frequency spectrum. These simulations reveal that gene diversity (heterozygosity) and mean pairwise differences are largely insensitive to events in recent population history, while statistics based on the number of haplotypes or segregating sites are much more sensitive. Overall, our analyses strongly indicate that the Icelandic gene pool is less heterogeneous than those of most other European populations.

• Soldevila M et al. Prion susceptibility and protective alleles exhibit marked geographic differences. In Hum Mutat (22(1):104-5). 2003.
  
• Stefansson H et al. Neuregulin 1 in schizophrenia: out of Iceland. In Mol Psychiatry (8(7):639-40). 2003.
  
• Helgason A et al. A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes. In Am J Hum Genet (72(6):1370-88). 2003.
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  Historical inferences from genetic data increasingly depend on assumptions about the genealogical process that shapes the frequencies of alleles over time. Yet little is known about the structure of human genealogies over long periods of time and how they depart from expectations of standard demographic models, such as that attributed to Wright and Fisher. To obtain such information and to examine the recent evolutionary history of mtDNA and Y-chromosome haplotypes in the Icelandic gene pool, we traced the matrilineal and patrilineal ancestry of all 131,060 Icelanders born after 1972 back to two cohorts of ancestors, one born between 1848 and 1892 and the other between 1798 and 1742. This populationwide coalescent analysis of Icelandic genealogies revealed highly positively skewed distributions of descendants to ancestors, with the vast majority of potential ancestors contributing one or no descendants and a minority of ancestors contributing large numbers of descendants. The expansion and loss of matrilines and patrilines has caused considerable fluctuation in the frequencies of mtDNA and Y-chromosome haplotypes, despite a rapid population expansion in Iceland during the past 300 years. Contrary to a widespread assumption, the rate of evolution caused by this lineage-sorting process was markedly faster in matrilines (mtDNA) than in patrilines (Y chromosomes). The primary cause is a 10% shorter matrilineal generation interval. Variance in the number of offspring produced within each generation was not an important differentiating factor. We observed an intergenerational correlation in offspring number and in the length of generation intervals in the matrilineal and patrilineal genealogies, which was stronger in matrilines and thus contributes to their faster evolutionary rate. These findings may have implications for coalescent date estimates based on mtDNA and Y chromosomes.

• Stefansson SE et al. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. In Am J Hum Genet (72(6):1448-59). 2003.
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  Osteoarthritis (OA) is the most common human joint disease, characterized by loss and/or remodeling of joint synovium, cartilage, and bone. Here, we describe a genomewide linkage analysis of patients with idiopathic hand OA who were carefully phenotyped for involvement of either or both the distal interphalangeal (DIP) joints and the first carpometacarpal (CMC1) joints. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected CMC1 joints (LOD = 4.97); this locus was also significant for patients with OA in both CMC1 and DIP joints (LOD = 4.44). The peak LOD score at this locus coincides with a gene, MATN3, encoding the noncollagenous cartilage extracellular matrix protein, matrilin-3. Subsequent screening of the genomic sequence revealed a missense mutation, of a conserved amino acid codon, changing threonine to methionine in the epidermal growth factor-like domain in matrilin-3. The missense mutation cosegregates with hand OA in several families. The mutation frequency is slightly more than 2% in patients with hand OA in the Icelandic population and has a relative risk of 2.1.

• Thorgeirsson TE et al. Anxiety with panic disorder linked to chromosome 9q in Iceland. In Am J Hum Genet (72(5):1221-30). 2003.
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  The results of a genomewide scan for genes conferring susceptibility to anxiety disorders in the Icelandic population are described. The aim of the study was to locate genes that predispose to anxiety by utilizing the extensive genealogical records and the relative homogeneity of the Icelandic population. Participants were recruited in two stages: (1) Initial case-identification by a population screening for anxiety disorders, using the Stamm Screening Questionnaire, was followed by aggregation into extended families, with the help of our genealogy database; and (2) those who fulfilled the diagnostic and family aggregation criteria underwent a more detailed diagnostic workup based on the Composite International Diagnostic Interview. Screening for anxiety in close relatives also identified additional affected members within the families. After genotyping was performed with 976 microsatellite markers, affected-only linkage analysis was done, and allele-sharing LOD scores were calculated using the program Allegro. Linkage analysis of 25 extended families, in each of which at least one affected individual had panic disorder (PD), resulted in a LOD score of 4.18 at D9S271, on chromosome 9q31. The intermarker distance was 4.4 cM on average, whereas it was 1.5 cM in the linked region as additional markers were added to increase the information content. The linkage results may be relevant not only to PD but also to anxiety in general, since our linkage study included patients with other forms of anxiety.

• Chrencik JE et al. Structural impact of the leukemia drug 1-beta-D-arabinofuranosylcytosine (Ara-C) on the covalent human topoisomerase I-DNA complex. In J Biol Chem (278(14):12461-6). 2003.
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  1-beta-d-Arabinofuranosylcytosine (Ara-C) is a potent antineoplastic drug used in the treatment of acute leukemia. Previous biochemical studies indicated the incorporation of Ara-C into DNA reduced the catalytic activity of human topoisomerase I by decreasing the rate of single DNA strand religation by the enzyme by 2-3-fold. We present the 3.1 A crystal structure of human topoisomerase I in covalent complex with an oligonucleotide containing Ara-C at the +1 position of the non-scissile DNA strand. The structure reveals that a hydrogen bond formed between the 2'-hydroxyl of Ara-C and the O4' of the adjacent -1 base 5' to the damage site stabilizes a C3'-endo pucker in the Ara-C arabinose ring. The structural distortions at the site of damage are translated across the DNA double helix to the active site of human topoisomerase I. The free sulfhydryl at the 5'-end of the nicked DNA strand in this trapped covalent complex is shifted out of alignment with the 3'-phosphotyrosine linkage at the catalytic tyrosine 723 residue, producing a geometry not optimal for religation. The subtle structural changes caused by the presence of Ara-C in the DNA duplex may contribute to the cytotoxicity of this leukemia drug by prolonging the lifetime of the covalent human topoisomerase I-DNA complex.

• Backman VM et al. HLA class II alleles and haplotypes in Icelandic Type I diabetic patients: comparison of Icelandic and Norwegian populations. In Diabetologia (45(3):452-3). 2003.
  
• Gudmundsdottir H. The road toward transplantation tolerance. In Transplant Proc (35(2):758-9). 2003.
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  Publication Types: Review Review, Tutorial.

• Hakonarson H et al. deCODE genetics, Inc. In Pharmacogenomics (4(2):209-15). 2003.
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  deCODE genetics, Inc. has compiled the world's most comprehensive collection of population data on genealogy, genotypes and phenotypes. This combination of resources provides an effective system for identifying key genes linked to common diseases and to the regulation of drug response. deCODE has successfully mapped genes in over 25 common complex diseases and isolated genes in eight of these. The methodology used to map these genes is based upon the company's genealogical database of the Icelandic population, which enables deCODE scientists to efficiently conduct population- and genome-wide linkage studies to identify key genetic factors involved in phenotypes ranging from diseases to drug response. In its growing pharmacogenomics program, deCODE has combined this linkage approach with high-throughput expression profiling to develop accurate tests that can predict individual responsiveness to virtually any drug of interest. deCODE is applying its unrivaled discovery capabilities to bring to market new drugs, DNA-based diagnostic products and pharmacogenomic tests. The company believes that such tests will play a crucial role in delivering personalized medicine - contributing to the development of more effective means of diagnosing and treating disease by matching each patient with the most suitable drug.

• Modin H et al. Genome-wide linkage screen of a consanguineous multiple sclerosis kinship. In Mult Scler (9(2):128-34). 2003.
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  Multiple sclerosis (MS), like Alzheimer's disease (AD) and Parkinson's disease (PD), is a common neurological disorder thought to be caused by the interaction of several genes with unknown environmental factors. In both AD and PD the identification of disease forms inherited in a classic Mendelian fashion has helped investigators elucidate pathogenetic mechanisms. In this study a whole-genome screen, with an average of 608 successful genotypes per person, was performed on nine members of a consanguineous family: the index case, three of her siblings and her daughter, all of whom have been diagnosed with definite MS; as well as the parents of the index case (first cousins), one of her five healthy siblings and her husband (who is also her first cousin). Nonparametric linkage analysis was performed on genotyping data. Based on the presence of consanguinity, the a priori hypothesis was that the disease is transmitted in an autosomal recessive fashion in the pedigree. Linkage analysis revealed a suggestive logarithm of odds (LOD) score of 2.29 on the long arm of chromosome 9. Four of five affected family members were identically homozygous for a haplotype under this peak, spanning approximately 43 cM, while the fifth affected subject and all unaffected family members were heterozygous for the haplotype.

• Gudjonsson JE et al. Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes. In Br J Dermatol (148(2):233-5). 2003.
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  BACKGROUND: Psoriasis is strongly associated with certain human leucocyte-associated antigens, especially HLA-Cw*0602. Patients who are HLA-Cw*0602 positive have been reported to have more active disease and a younger age at disease onset than HLA-Cw6-negative patients. OBJECTIVES: To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients. METHODS: One thousand and six patients with chronic plaque psoriasis were evaluated clinically and HLA-C typed. In addition, 512 unrelated controls were typed for HLA-C. RESULTS: Of the patients 646 (64.2%) were HLA-Cw*0602 positive, and 68 (6.8%) were homozygous for this allele. Heterozygosity was associated with a relative risk of developing psoriasis of 8.9 compared with 23.1 for the Cw6 homozygous patients. The homozygous patients also had an earlier disease onset (mean 15.0 vs. 17.8 years, P = 0.04). However, the Cw6 homozygotes did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes or any other clinical parameter recorded. CONCLUSIONS: Homozygosity for the gene in the major histocompatibility complex region has a major additive impact on the risk of developing psoriasis and predisposes to an earlier disease onset, but does not have any marked influence on the phenotype or the severity of the disease.

• Jonsson H et al. The inheritance of hand osteoarthritis in Iceland. In Arthritis Rheum (48(2):391-5). 2003.
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  OBJECTIVE: To assess the contribution of genetics to hand osteoarthritis (HOA) and its subsets in the Icelandic population. METHODS: A list of 2,919 HOA patients, constituting 1% of the Icelandic population, was compiled through nationwide sources. This patient list was cross-referenced with a comprehensive Icelandic genealogy database, enabling the use of algorithms to assess familiality of HOA. Two methods were used: the average pairwise kinship coefficient (KC) of the patients, and the relative risk (RR) of HOA in relatives of patients. In each case, the results were compared with 1,000 control sets of similar composition with regard to number, age, and sex, generated from the genealogy database. RESULTS: The KC for patients was significantly higher than for the control sets and was proportional to the degree of both interphalangeal (IP) and thumb base (first carpometacarpal [CMC] joint) involvement. The RR of HOA in sisters of women in the study was 2.0 (P < 0.001), while the RR in spouses was not significantly different from that in controls. The RR increased with the severity of the disease. Thus, sisters of women with severe IP HOA had an RR of 5.0 and sisters of those with severe first CMC involvement had an RR of 6.9. The increased risk also extended beyond the nuclear family, with significantly increased risk in cousins. CONCLUSION: Patients seeking medical services for HOA are more related to each other than matched controls, supporting the role of a genetic component in the disease. The genetic influence in both IP and first CMC HOA appears to be similar and increases with increasing severity of the disease.

• Karason A et al. A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. In Am J Hum Genet (72(1):125-31). 2003.
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  Several genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.

• Stefansson H et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. In Am J Hum Genet (72(1):83-7). 2003.
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  Recently, we identified neuregulin 1 (NRG1) as a susceptibility gene for schizophrenia in the Icelandic population, by a combined linkage and association approach. Here, we report the first study evaluating the relevance of NRG1 to schizophrenia in a population outside Iceland. Markers representing a core at-risk haplotype found in Icelanders at the 5' end of the NRG1 gene were genotyped in 609 unrelated Scottish patients and 618 unrelated Scottish control individuals. This haplotype consisted of five SNP markers and two microsatellites, which all appear to be in strong linkage disequilibrium. For the Scottish patients and control subjects, haplotype frequencies were estimated by maximum likelihood, using the expectation-maximization algorithm. The frequency of the seven-marker haplotype among the Scottish patients was significantly greater than that among the control subjects (10.2% vs. 5.9%, P=.00031). The estimated risk ratio was 1.8, which is in keeping with our report of unrelated Icelandic patients (2.1). Three of the seven markers in the haplotype gave single-point P values ranging from .000064 to .0021 for the allele contributing to the at-risk haplotype. This direct replication of haplotype association in a second population further implicates NRG1 as a factor that contributes to the etiology of schizophrenia.