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Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91 phox ) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1 . Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland ( P   =  8.3 × 10 −8 ; OR = 67.6), as well as reduced height ( P   =  3.3 × 10 −4 ; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction. Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.

Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P= 1.9 × 10 −18 , odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P= 1.5 × 10 −10 , OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P= 3.0 × 10 −11 , OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study. A hallmark of diverticular disease is pouches in the bowel wall which can become infected and inflamed, causing the more severe diverticulitis. Here, the authors report the first genome-wide association study on these interconnected conditions and identify ARHGAP15 , COLQ and FAM155A as novel risk loci.

Kari Stefansson and colleagues identify a nonsense mutation in RBM12 segregating with psychosis in an extended Icelandic pedigree and an independent frameshift mutation in RBM12 segregating with psychosis in a Finnish family. They further show that carriers of the Icelandic mutation who are unaffected by psychosis exhibit a psychiatric disorder and cognitive test battery profile resembling that of patients with schizophrenia. Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T ( P = 2.2 × 10 −4 ), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis ( P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile ( P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.

The genomes of ancient humans can reveal patterns of early human migration (see the Perspective by Achilli et al. ). Iceland has a genetically distinct population, despite relatively recent settlement (∼1100 years ago). Ebenesersdóttir et al. examined the genomes of ancient Icelandic people, dating to near the colonization of Iceland, and compared them with modernday Icelandic populations. The ancient DNA revealed that the founders had Gaelic and Norse origins. Genetic drift since the initial settlement has left modern Icelanders with allele frequencies that are distinctive, although still skewed toward those of their Norse founders. Scheib et al. sequenced ancient genomes from the Channel Islands of California, USA, and Ontario, Canada. The ancient Ontario population was similar to other ancient North Americans, as well as to modern Algonquian-speaking Native Americans. In contrast, the California individuals were more like groups that now live in Mexico and South America. It appears that a genetic split and population isolation likely occurred during the Ice Age, but the peoples remixed at a later date. Science , this issue p. 1028 , p. 1024 ; see also p. 964 Genetic drift and mixing of peoples from Norway and the British Isles gave rise to the modern Icelandic population. Opportunities to directly study the founding of a human population and its subsequent evolutionary history are rare. Using genome sequence data from 27 ancient Icelanders, we demonstrate that they are a combination of Norse, Gaelic, and admixed individuals. We further show that these ancient Icelanders are markedly more similar to their source populations in Scandinavia and the British-Irish Isles than to contemporary Icelanders, who have been shaped by 1100 years of extensive genetic drift. Finally, we report evidence of unequal contributions from the ancient founders to the contemporary Icelandic gene pool. These results provide detailed insights into the making of a human population that has proven extraordinarily useful for the discovery of genotype-phenotype associations.

Objectives The aim was to study the cause-specific mortality of users of the emergency department (ED) who received a diagnosis of alcohol use disorder (AUD) in comparison with mortality of other users of the department. Design A population-based prospective cohort study. Participants All patients aged 18 years and above who were subsequently discharged home from the ED during the years 2002–2008. A total of 107 237 patients were followed by record linkage to a nationwide cause-of-death registry: 1210 patients with AUD as the main discharge diagnosis and 106 027 patients in the comparison group. HR and 95% CIs were calculated. Setting ED at Landspitali—the National University Hospital of Iceland, Reykjavik, Iceland. The hospital offers tertiary care and is the number one trauma centre and community hospital for the greater Reykjavik area. According to the population registry, 78% of the inhabitants of the area attended the ED during the study period. Results 72 patients died in the AUD group and 4807 in the comparison group. The adjusted HR for all causes of death was 1.91 (95% CI 1.51 to 2.42). The HR for AUDs was 47.68 (95% CI 11.56 to 196.59) while for alcohol liver disease the HR was 19.06 (95% CI 6.07 to 59.87). The HR was also elevated for diseases of the circulatory system: HR 2.52 (95% CI 1.73 to 3.68); accidental poisoning: HR=13.64, (95% CI 3.98 to 46.73); suicide: HR=2.72 (95% CI 1.08 to 6.83); and event of undetermined intent: HR=10.89 (95% CI 4.53 to 26.16). Conclusions AUD as the discharge diagnosis at the ED, among patients who were not admitted to a hospital ward but discharged home, predicts increased mortality. As the results conclusively show the vulnerability of these patients, one can question whether their needs are adequately met at the ED.