Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank3. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.

Objectives:To assess the impact of increased number of diagnostic and therapeutic joint procedures on the incidence and type of septic arthritis (SA).Methods:All cases of SA in Iceland from 1990–2002 were identified by thorough review of the available medical information. The results of synovial fluid cultures from every microbiology department in Iceland were checked and positive culture results reviewed, as well as patient charts with a discharge diagnosis of septic arthritis (International Statistical Classification of Diseases and Related Health Problems (ICD) code M009).Results:A total of 253 cases of SA (69 children and 184 adults) were diagnosed in Iceland in 1990–2002, giving an average incidence of 7.1 cases/100 000 inhabitants. The incidence of SA increased from 4.2 cases/100 000 in 1990 to 11.0 cases/100 000 in 2002. This rise in SA was primarily observed in adults where the incidence rose by 0.61 cases/100 000 per year (p<0.001). SA was iatrogenic in 41.8% of adults and the number of iatrogenic infections increased from 2.8 cases/year in 1990–1994 to 9.0 cases/year in 1998–2002 (p<0.01). The annual number of arthroscopies increased from 430 in 1990–1994 to 2303 in 1998–2002 (p<0.001) and there was a correlation between the total usage of intra-articular drugs in Iceland and the incidence of SA (p<0.01). The frequency of post-arthroscopy SA was 0.14% and post-arthrocentesis SA 0.037%.Conclusions:The incidence of SA has increased in recent years due to an increased number of arthroscopies and joint injections. Although the frequency of SA per procedure has not changed, these results emphasise the importance of sterile technique and firm indications for joint procedures.

More than half of all oesophageal injuries in Iceland are caused by a iatrogenic injury. Mortality is significant and is related to a missed diagnosis. Patients treated surgically all survived surgery; however, complications were frequent and their hospital stay was long.

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.