Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

The common sequence variants that have recently been associated with cancer risk are particular to a single, or at most two, cancer types. Following up on our genome-wide scan of basal cell carcinoma1, we identified rs401681(C) on chromosome 5p15.33 satisfying our threshold for genome-wide significance (OR=1.25, P=3.7×10−12). We tested rs401681 for association with sixteen additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR=1.15, P=7.2×10−8) and urinary bladder, prostate and cervix cancer (ORs 1.07–1.31, all P<4×10−4). However, rs401681(C) appears to confer protection against cutaneous melanoma (OR=0.88, P=8.0×10−4). Interestingly, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098(A), that showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. Rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein while rs401681 is in an intron of the CLPTM1L gene.

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genomewide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10 −27 ) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10 −9 ). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T 4 ) and high concentration of triiodothyronine (T 3 ).Thyroid carcinoma is the most common endocrine malignancy, and its incidence in industrialized countries has been rising over the past few decades: at present, its incidence is 4.9 and 14.1 per 100,000 in the United States for males and females of European ancestry, respectively (see URLs section in Methods). It has been determined that the risk of thyroid cancer has a greater genetic component than the risk of any other cancer, and the effect has been shown to extend beyond the nuclear family 1-3 . The risk has been reported to be highest for first-degree male relatives of male probands but lowest for first-degree female relatives of female probands 4 . Not much is known about variants in the sequence of the genome that affect the risk of thyroid cancer. However, recently variants at 1p12, 8q24 and in the premiR146a at 5q33 have been implicated in the disease 5-8 .Thyroid cancer is classified histologically into four main groups: papillary (PTC), follicular (FTC), medullary (MTC) and undifferentiated or anaplastic thyroid carcinomas. Most of all thyroid tumors are PTC (80-85%) or FTC (10-15%) 9,10 . Among established risk factors for FTC is deficiency in iodine intake, and for PTC the risk factors include ionizing radiation, nodular disease of the thyroid as well as family history 9 . Medullary thyroid cancer is a part of the multiple endocrine neoplasia type 2 syndrome (MEN2) and accounts for about 1-3% of all thyroid cancer cases. Its pathogenesis can mainly be explained by mutations in the RET oncogene 11 . Anaplastic thyroid cancer accounts for between 1% and 5% of all carcinomas of the thyroid. This subphenotype is one of the most aggressive of all human malignancies, but little is known about its pathogenesis 12 .In Iceland, the annual incidence of thyroid cancer is similar to that in the United States, at 4.6 and 12.1 per 100,000 for males and fe...

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.