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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 2006

• Thomsen LL et al. The genetic spectrum of a population-based sample of familial hemiplegic migraine. In Brain. 2006.
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  Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura and transient hemiplegia. FHM mutations are known in three genes, the CACNA1A (FHM1) gene, the ATP1A2 (FHM2) and the SCN1A (FHM3) gene and seem to have an autosomal-dominant mode of inheritance. The aim of this study was to search for FHM mutations in FHM families identified through a screen of the Danish population of 5.2 million people. FHM patients were diagnosed according to the International Classification of Headache Disorders and all FHM patients had a physical and neurological examination by a physician. A total of 147 FHM patients from 44 different families were identified; 43 FHM families participated in this study. Linkage analysis of these families shows clear linkage to the FHM locus (FHM1) on chromosome 19, supportive linkage to the FHM2 locus whereas no linkage was found to the FHM3 locus. Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene. CACNA1A gene mutations were identified in three of the FHM families, two known FHM mutations, R583Q and T666M and one novel C1369Y mutation. Three FHM families were identified with novel mutations in the ATP1A2 gene; a family with a V138A mutation, a family with a R202Q mutation and a family with a R763C mutation. None of the Danish FHM families have the Q1489K mutation in the SCN1A gene. Our study shows that only 14% (6/42) of FHM families in the general Danish population have exonic FHM mutations in the CACNA1A or ATP1A2 gene. The families we identified with FHM mutations in the CACNA1A and ATP1A2 genes were extended, multiple affected families whereas the remaining FHM families were smaller. The existence of many small families in the Danish FHM cohort may reflect less bias in FHM family ascertainment and/or more locus heterogeneity than described previously.

• Kirchmann M et al. Validation of the deCODE Migraine Questionnaire (DMQ3) for use in genetic studies. In Eur J Neurol (13(11):1239-44). 2006.
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  We assessed the reliability of the diagnosis of migraine with aura (MA) and migraine without aura (MO) based on the third edition of the deCODE Migraine Questionnaire (DMQ3) using a physician-conducted interview as an empirical index of validity. Amongst Danish migraine families recruited from specialist practice we selected 200 cases diagnosed according to the International Classification of Headache Disorders 2nd Edition in a validated physician-conducted telephone interview: 50 patients with exclusively MA, 50 with both MA and MO, 50 with exclusively MO and 50 controls. A written copy of the DMQ3 was mailed to the participant. The DMQ3-based diagnosis was compared with the interview-based diagnosis. Overall, the DMQ3 diagnosed migraine (MA, MO or both) with a sensitivity of 99% (109/110), a specificity of 86% (32/37) and a kappa statistic of 0.89. The most reliable subtype of migraine was MA (with or without co-occurring attacks of MO) which was diagnosed with a sensitivity of 92% (71/77), a specificity of 93% (65/70) and a kappa statistic of 0.85. Exclusively MO was diagnosed with a sensitivity of 91% (30/33), a specificity of 93% (106/114) and a kappa statistic of 0.80. Weakest was the diagnosis of both MO and MA which was diagnosed with a sensitivity of 63% (24/38), a specificity of 92% (100/109) and a kappa statistic of 0.57. In conclusion, the DMQ3 is a valid tool for diagnosing patients with migraine for genetic studies.

• Gulcher JR et al. Reply to "Many hypotheses but no replication for the association between PDE4D and stroke". In Nat Genet (38(10):1092-3). 2006.
  
• Stacey SN et al. The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland. In PLoS Med (3(7), e217). 2006.
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  Most, if not all, of the cellular functions of the BRCA1 protein are mediated through.

  heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breastcancer-.

  associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1.

  complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility.

  to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at.

  increased frequencies in breast cancer families. We investigated the role of the BARD1.

  Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast.

  cancer and 703 controls. We then used a computerized genealogy of the Icelandic population.

  to study the relationships between the Cys557Ser variant and familial clustering of breast.

  cancer.

• Amundadottir LT et al. A common variant associated with prostate cancer in European and African populations. In Nat Genet (38(6):652-8). 2006.
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  With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

• Gudjonsson JE et al. Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients. In J Invest Dermatol (126(4):740-5). 2006.
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  A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque psoriasis. The patients were typed for HLA-C and HLA-B. A total of 654 (64.2%) were HLA-Cw*0602 positive but 365 (35.8%) carried other HLA-C alleles. We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P<10(-10)), higher incidence of guttate and the eruptive type of psoriasis (P<0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner's phenomenon (P=0.01), and more extensive disease (P=0.03). A striking new finding was a diverging pattern of disease severity in HLA-Cw*0602 positive and negative patients depending on the age of onset of the disease (P=0.0006). HLA-Cw*0602 positive women also had more frequent remissions during pregnancy (P<0.0001). All types of nail changes were, however, more common in the Cw*0602 negative patients (P=0.003) and they more often had multiple types of nail lesions (P<0.0001). The three ancestral haplotypes of Cw*0602 all conferred an increase in odds ratio but showed no difference in any of the clinical features studied. Our findings indicate that the genetic factor on chromosome 6 has a strong influence on the phenotype of the disease, and underline that differences in clinical features of psoriasis may be to a large extent genetically determined.

• Arnar DO et al. Familial aggregation of atrial fibrillation in Iceland. In Eur Heart J (27(6):708-12). 2006.
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  AIMS: To examine the heritability of atrial fibrillation (AF) in Icelanders, utilizing a nationwide genealogy database and population-based data on AF. AF is a disorder with a high prevalence, which has been known to cluster in families, but the heritability of the common form has not been well defined. METHODS AND RESULTS: The study population included 5269 patients diagnosed since 1987 and age-sex-matched controls randomly selected from the genealogy database. Kinship coefficients (KC), expressed as genealogical index of familiality (GIF = average KC x 100,000), were calculated before and after exclusion of relatives separated by one to five meiotic events. Risk ratios (RR) were calculated for first- to fifth-degree relatives. The average pairwise GIF among patients with AF was 15.9 (mean GIF for controls 13.9, 95%CI = 13.3, 14.4); this declined to 15.4 (mean GIF for controls 13.6, 95%CI = 13.1, 14.2) after exclusion of relatives separated by one meiosis and to 13.7 (mean GIF for controls 12.6, 95%CI = 12.1, 13.2), 12.7 (mean GIF for controls 11.9, 95%CI = 11.4, 12.4), and 11.3 (mean GIF for controls 10.6, 95%CI = 10.1, 11.1) after exclusion of relatives within two, three, and four meioses, respectively (all P<0.00001). RRs among relative pairs also declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives (all P<0.001), consistent with the declining proportion of alleles shared identically by descent. When the analysis was limited to subjects diagnosed with AF before the age of 60, first-degree relatives of the AF cases were nearly five times more likely to have AF than the general population. CONCLUSION: AF shows strong evidence of heritability among unselected patients in Iceland, suggesting that there may be undiscovered genetic variants underlying the risk of the common form of AF.

• Grant SF et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. In Nat Genet (38(3):320-3). 2006.
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  We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.

• Sainz J et al. Segmental duplication density decrease with distance to human-mouse breaks of synteny. In Eur J Hum Genet (14(2):216-21). 2006.
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  Segmental duplications are large genomic segments of recent origin and nearly identical sequence. Segmental duplications account for up to 5% of the human genome and they are often involved in genomic rearrangements and human disease. We developed a rapid computational method to characterize segmental duplications in the mouse and the human genomes according to four sequence assemblies for each species. Segmental duplication content in the mouse genome assemblies has largely changed over the four releases (from 0.2 to 1.2%, 4.5 and 3.0%), while in the four human assemblies duplication content was 4.8, 3.5, 3.7 and 3.7%, respectively. This suggests that cataloguing and assembling duplications has been challenging in both genomes and any interpretation of comparative analyses of duplication content must keep this in perspective to avoid artifacts. Human and mouse segmental duplications are more frequent than expected in regions where there is a syntenic discontinuity and the duplication content in syntenic regions decreases significantly with distance from breakpoints of synteny. These observations indicate that in mouse and human the frequency of segmental duplications is strongly correlated with distance to human and mouse syntenic breaks or the most dynamic regions in evolution..

• Bergthorsson JT et al. A genome-wide study of allelic imbalance in human testicular germ cell tumors using microsatellite markers. In Cancer Genet Cytogenet (1;164(1):1-9). 2006.
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  Testicular germ cell tumors (TGCT) arise by multistep carcinogenesis pathways involving selective losses and gains of chromosome material. To locate cancer genes underlying this selection, we performed a genome-wide study of allelic imbalance (AI) in 32 tumors, using 710 microsatellite markers. The highest prevalence of AI was found at 12p, in line with previous studies finding consistent gain of the region in TGCTs. High frequency of AI was also observed at chromosome arms 4p, 9q, 10p, 11q, 11p, 13q, 16q, 18p, and 22q. Within 39 candidate regions identified by mapping of smallest regions of overlap (SROs), the highest frequency of AI was at 12p11.21 approximately p11.22 (62%), 12p12.1 approximately p13.1 (53%), 12p13.1 approximately p13.2 (53%), 11q14.1 approximately q14.2 (53%), 11p13 approximately p14.3 (47%), 9q21.13 approximately q21.32 (47%), and 4p15.1 approximately p15.2 (44%). Two genes known to be involved in cancer reside in these regions, ETV6 at 12p13.2 (TEL oncogene) and WT1 at 11p13. We also found a significant association (P = 0.02) between AI at 10q21.1 approximately q22.2 and higher clinical stage. This study contributes to the ongoing search for genes involved in transformation of germ cells and provides a useful reference point to previous studies using cytogenetic techniques to map chromosome changes in TGCTs.

• Helgadottir A et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. In Nat Genet. 2006.
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  Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction1. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.

• Magnusson KP et al. CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. In PLoS Med (3(1):e5). 2006.
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  BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD--or the relationship between them--is unclear. METHODS AND FINDINGS: We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 x 10(-12)) and odds ratio of 2.14 in US patients from Utah (p = 2.0 x 10(-9)) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). CONCLUSION: Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.

• Gulcher J, Stefansson K. Positional cloning: complex cardiovascular traits. In Methods Mol Med (128:137-52). 2006.
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  Cardiovascular traits represent the quintessential complex trait derived from the confluence of numerous genetic and environmental risk factors. Therefore, positional cloning of cardiovascular genes contributing to the common forms of cardiovascular disease is much more challenging than the mapping and isolation of genes contributing to rare Mendelian phenocopies of cardiovascular disease. Success requires careful and systematic phenotyping, large numbers of families that contain multiple patients, and high-quality genotyping covering for both genome scan and the follow-up case-control association study testing the genes and LD blocks within the linkage peaks.

• Helgason A et al. mtDNA variation in Inuit populations of Greenland and Canada: Migration history and population structure. In Am J Phys Anthropol. 2006.
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  We examined 395 mtDNA control-region sequences from Greenlandic Inuit and Canadian Kitikmeot Inuit with the aim of shedding light on the migration history that underlies the present geographic patterns of genetic variation at this locus in the Arctic. In line with previous studies, we found that Inuit populations carry only sequences belonging to haplotype clusters A2 and D3. However, a comparison of Arctic populations from Siberia, Canada, and Greenland revealed considerable differences in the frequencies of these haplotypes. Moreover, large sample sizes and regional information about birthplaces of maternal grandmothers permitted the detection of notable differences in the distribution of haplotypes among subpopulations within Greenland. Our results cast doubt on the prevailing hypothesis that contemporary Inuit trace their all of their ancestry to so-called Thule groups that expanded from Alaska about 800-1,000 years ago. In particular, discrepancies in mutational divergence between the Inuit populations and their putative source mtDNA pool in Siberia/Alaska for the two predominant haplotype clusters, A2a and A2b, are more consistent with the possibility that expanding Thule groups encountered and interbred with existing Dorset populations in Canada and Greenland. Am J Phys Anthropol, 2006. (c) 2005 Wiley-Liss, Inc.