• Article
    | Open Access

    Deep phenotype and genome-wide genetic data from 500,000 individuals from the UK Biobank, describing population structure and relatedness in the cohort, and imputation to increase the number of testable variants to 96 million.

    • Clare Bycroft
    • , Colin Freeman
    •  & Jonathan Marchini
  • Letter |

    A genome-wide association study of approximately 7,000 patients with neurodevelopmental disorders demonstrates that overall risk and clinical presentation in putative monogenic disorders is also influenced by common genetic variants present in the general population.

    • Mari E. K. Niemi
    • , Hilary C. Martin
    •  & Jeffrey C. Barrett
  • Letter |

    Exome sequence analysis of nearly 10,000 people was carried out to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) were associated with disease risk, identifying the key roles of low-density lipoprotein cholesterol and metabolism of triglyceride-rich lipoproteins.

    • Ron Do
    • , Nathan O. Stitziel
    •  & Sekar Kathiresan
  • Letter |

    Rare truncating mutations in the p53-inducible protein phosphatase PPM1D are shown to be associated with predisposition to breast cancer and ovarian cancer; notably, all of the mutations are mosaic in white blood cells but are not present in tumours, and probably have a gain-of-function effect.

    • Elise Ruark
    • , Katie Snape
    •  & Nazneen Rahman
  • Letter |

    A non-coding region on chromosome 9p21 was previously shown to associate with coronary artery disease and type 2 diabetes, and the region has been implicated in regulating neighbouring genes. Here, 33 distinct enhancers within this region are identified, showing that SNPs in one of the enhancers affect STAT1 binding. Furthermore, it is shown that in human vascular endothelial cells the enhancer interval physically interacts with a number of specific loci and that IFN-γ activation strongly affects the chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions and expression of neighbouring genes.

    • Olivier Harismendy
    • , Dimple Notani
    •  & Kelly A. Frazer
  • Article |

    Impulsive behaviour characterizes several psychiatric diseases and violent behaviour but its origins are complex. Here, exon sequencing focused on fourteen serotonin- and dopamine-related genes identified a mutation in HTR2B, which was associated with psychiatric diseases marked by impulsivity in a Finnish population. The role of this serotonin receptor in impulsivity is further supported by the knockout mouse phenotype.

    • Laura Bevilacqua
    • , Stéphane Doly
    •  & David Goldman
  • Letter |

    Here, single nucleotide variants within the LMO1 locus are shown to be associated with inherited susceptibility to neuroblastoma, a childhood cancer of the sympathetic nervous system. Acquired structural variation in the same locus was also frequently found in neuroblastoma patients, leading to the suggestion that loci identified through genome-wide association studies might be also prone to somatic alterations and therefore identify potential therapy targets and/or biomarkers of tumour aggressiveness.

    • Kai Wang
    • , Sharon J. Diskin
    •  & John M. Maris
  • Article |

    The causes of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood, although the protein TDP-43 seems to be involved. These authors show that the polyglutamine-containing protein ataxin 2 interacts with TDP-43 and is a potent modifier of TDP-43 toxicity. Moreover, intermediate-length polyglutamine expansions in the ataxin 2 gene significantly associate with ALS. These data establish the ataxin 2 gene as a new and relatively common ALS disease susceptibility gene.

    • Andrew C. Elden
    • , Hyung-Jun Kim
    •  & Aaron D. Gitler
  • Letter |

    Sialic acid acetylesterase (SIAE) is an enzyme that is involved in B-cell activation and is required to maintain immunological tolerance in mice. It is shown here that rare, inherited and functionally defective SIAE variants are associated with a variety of autoimmune diseases in humans. The study provides one of the first examples of the importance of rare genetic variants in complex diseases, such as those involving autoimmunity.

    • Ira Surolia
    • , Stephan P. Pirnie
    •  & Shiv Pillai
  • Letter |

    An extensive genome-wide survey of over 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf, was conducted to shed light on the process of dog diversification. The results reveal that much of genome diversity came from Middle Eastern progenitors, combined with interbreeding with local wolf populations, and that recent evolution involved limited genetic variation to create the phenotypic diversity of modern dogs.

    • Bridgett M. vonHoldt
    • , John P. Pollinger
    •  & Robert K. Wayne
  • Letter |

    The existence of all-female species of whiptail lizard, formed as a hybrid between sexual species, has been known since 1962; however, how the meiotic program is altered to produce diploid eggs while maintaining heterozygosity has remained unclear. Here it is shown in parthenogenetic species that meiosis initiates with twice the number of chromosomes compared to sexual species, and that pairing and recombination takes place between genetically identical sister chromosomes instead of between homologues.

    • Aracely A. Lutes
    • , William B. Neaves
    •  & Peter Baumann