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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 2007

• Sulem P et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. In Nat Genet. 2007.
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  Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions-four not previously implicated in the normal variation of human pigmentation-and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R.

• Gudmundsson J et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. In Nat Genet (39(8):977-83). 2007.
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  We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

• Stefansson H et al. A Genetic Risk Factor for Periodic Limb Movements in Sleep. In N Engl J Med (357(7):639-47). 2007.
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  Background The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. .

  Methods To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. .

  Results In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10¿9). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10¿4) and a U.S. sample (odds ratio, 1.5; P=4x10¿3). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10¿17). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). .

  Conclusions We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.

• Thorleifsson G et al. Common Sequence Variants in the LOXL1 Gene Confer Susceptibility to Exfoliation Glaucoma. In Science. 2007.
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  Glaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple SNPs in the 15q24.1 region associated to glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two non-synonymous SNPs in exon 1 of the gene LOXL1 explain the association and the data suggest that they confer risk to XFG mainly through exfoliation syndrome (XFS). Approximately 25% of the general population is homozygous for the highest risk haplotype and their risk of suffering XFG is over 100 times that of those only carrying low-risk haplotypes. The population attributable risk (PAR) is over 99%. The product of LOXL1 catalyses the formation of elastin fibers found to be a major component of the lesions in XFG.

• Gudbjartsson DF et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. In Nature (448(7151:353-7). 2007.
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  Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.

• Steinthorsdottir V et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. In Nat Genet (39(6):770-5). 2007.
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  We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants1, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13¿1.27), P = 7.7 × 10¿9) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11¿1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31¿1.72) and 1.55 (1.23¿1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

• Gudmundsson J et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. In Nat Genet (39(5):631-7). 2007.
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  Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions1, with African American men having among the highest worldwide incidence and mortality rates2. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered3, accounts for about 11%¿13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%¿4%) susceptibility variant in individuals of European descent that happens to be very common (42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.

• Helgadottir A et al. A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction. In Science. 2007.
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  The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,769 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated to the disease with high significance (P = 1.2 x 10(-20)). Approximately 21% of individuals in the population are homozygous for this variant and they have an estimated 1.64-fold greater risk of suffering myocardial infarction than non-carriers. The corresponding risk is 2.02-fold for early onset cases. The population attributable risk (PAR) is 21% for MI in general and 31% for early onset cases.

• Stacey SN et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. In Nat Genet. 2007.
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  Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

  PMID: 17529974 [PubMed - as supplied by publisher].

• Bjarnadottir M et al. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/- knock-outs compared with wild-type mice. In The Journal of Neuroscience (27(17):4519-4529). 2007.
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  We previously identified Neuregulin1 (NRG1) as a gene contributing to the risk of developing schizophrenia. Furthermore, we showed that NRG1+/- mutant mice display behavioral abnormalities that are reversed by clozapine, an atypical antipsychotic drug used for the treatment of schizophrenia. We now present evidence that ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4), the tyrosine kinase receptor for NRG1 in hippocampal neurons, interacts with two nonreceptor tyrosine kinases, Fyn and Pyk2 (proline-rich tyrosine kinase 2). NRG1 stimulation of cells expressing ErbB4 and Fyn leads to the association of Fyn with ErbB4 and consequent activation. Furthermore, we show that NRG1 signaling, through activation of Fyn and Pyk2 kinases, stimulates phosphorylation of Y1472 on the NR2B subunit of the NMDA receptor (NMDAR), a key regulatory site that modulates channel properties. NR2B Y1472 is hypophosphorylated in NRG1+/- mutant mice, and this defect can be reversed by clozapine at a dose that reverses their behavioral abnormalities. We also demonstrate that short-term synaptic plasticity is altered and theta-burst long-term potentiation is impaired in NRG1+/- mutant mice, and incubation of hippocampal slices from these mice with NRG1 reversed those effects. Attenuated NRG1 signaling through ErbB4 may contribute to the pathophysiology of schizophrenia through dysfunction of NMDAR modulation. Thus, our data support the glutamate hypothesis of schizophrenia.

• Helgason A et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. In Nat Genet (39(2):218-25). 2007.
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  We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%¿28% in three populations of European ancestry1. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapBT2D, to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.